The present invention relates to novel compounds, compositions, and methods for the treatment of psychiatric disorders and neurological diseases, including major depression, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy and feeding disorders, as well as treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress. In particular, the present invention relates to novel imidazopyrimidines and imidazopyridines, pharmaceutical compositions containing such compounds and their use in treating psychiatric disorders, neurological diseases, immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress.
Corticotropin releasing factor (herein referred to as CRF), a 41 amino acid peptide, is the primary physiological regulator of proopiomelanocortin (POMC)xe2x80x94derived peptide secretion from the anterior pituitary gland [J. Rivier et al., Proc. Nat. Acad. Sci. (USA) 80:4851 (1983); W. Vale et al., Science 213:1394 (1981)]. In addition to its endocrine role at the pituitary gland, immunohistochemical localization of CRF has demonstrated that the hormone has a broad extrahypothalamic distribution in the central nervous system and produces a wide spectrum of autonomic, electrophysiological and behavioral effects consistent with a neurotransmitter or neuromodulator role in brain [W. Vale et al., Rec. Prog. Horm. Res. 39:245 (1983); G. F. Koob, Persp. Behav. Med. 2:39 (1985); E. B. De Souza et al., J. Neurosci. 5:3189 (1985)]. There is also evidence that CRF plays a significant role in integrating the response of the immune system to physiological, psychological, and immunological stressors [J. E. Blalock, Physiological Reviews 69:1 (1989); J. E. Morley, Life Sci. 41:527 (1987)].
Clinical data provide evidence that CRF has a role in psychiatric disorders and neurological diseases including depression, anxiety-related disorders and feeding disorders. A role for CRF has also been postulated in the etiology and pathophysiology of Alzheimer""s disease, Parkinson""s disease, Huntington""s disease, progressive supranuclear palsy and amyotrophic lateral sclerosis as they relate to the dysfunction of CRF neurons in the central nervous system [for review see E. B. De Souza, Hosp. Practice 23:59 (1988)].
In affective disorder, or major depression, the concentration of CRF is significantly increased in the cerebral spinal fluid (CSF) of drug-free individuals [C. B. Nemeroff et al., Science 226:1342 (1984); C. M. Banki et al., Am. J. Psychiatry 144:873 (1987); R. D. France et al., Biol. Psychiatry 28:86 (1988); M. Arato et al., Biol Psychiatry 25:355 (1989)]. Furthermore, the density of CRF receptors is significantly decreased in the frontal cortex of suicide victims, consistent with a hypersecretion of CRF [C. B. Nemeroff et al., Arch. Gen. Psychiatry 45:577 (1988)]. In addition, there is a blunted adrenocorticotropin (ACTH) response to CRF (i.v. administered) observed in depressed patients [P. W. Gold et al., Am J. Psychiatry 141:619 (1984); F. Holsboer et al., Psychoneuroendocrinology 9:147 (1984); P. W. Gold et al., New Eng. J. Med. 314:1129 (1986)]. Preclinical studies in rats and non-human primates provide additional support for the hypothesis that hypersecretion of CRF may be involved in the symptoms seen in human depression [R. M. Sapolsky, Arch. Gen. Psychiatry 46:1047 (1989)]. There is preliminary evidence that tricyclic antidepressants can alter CRF levels and thus modulate the numbers of CRF receptors in brain [Grigoriadis et al., Neuropsychopharmacology 2:53 (1989)].
It has also been postulated that CRF has a role in the etiology of anxiety-related disorders. CRF produces anxiogenic effects in animals and interactions between benzodiazepine/non-benzodiazepine anxiolytics and CRF have been demonstrated in a variety of behavioral anxiety models [D. R. Britton et al., Life Sci. 31:363 (1982); C. W. Berridge and A. J. Dunn Regul. Peptides 16:83 (1986)]. Preliminary studies using the putative CRF receptor antagonist a-helical ovine CRF (9-41) in a variety of behavioral paradigms demonstrate that the antagonist produces xe2x80x9canxiolytic-likexe2x80x9d effects that are qualitatively similar to the benzodiazepines [C. W. Berridge and A. J. Dunn Horm. Behav. 21:393 (1987), Brain Research Reviews 15:71 (1990)].
Neurochemical, endocrine and receptor binding studies have all demonstrated interactions between CRF and benzodiazepine anxiolytics, providing further evidence for the involvement of CRF in these disorders. Chlordiazepoxide attenuates the xe2x80x9canxiogenicxe2x80x9d effects of CRF in both the conflict test [K. T. Britton et al., Psychopharmacology 86:170 (1985); K. T. Britton et al., Psychopharmacology 94:306 (1988)] and in the acoustic startle test [N. R. Swerdlow et al., Psychopharmacology 88:147 (1986)] in rats. The benzodiazepine receptor antagonist (Rol5-1788), which was without behavioral activity alone in the operant conflict test, reversed the effects of CRF in a dose-dependent manner while the benzodiazepine inverse agonist (FG7142) enhanced the actions of CRF [K. T. Britton et al., Psychopharmacology 94:306 (1988)].
It has been further postulated that CRF has a role in immunological, cardiovascular or heart-related diseases such as hypertension, tachycardia and congestive heart failure, stroke, osteoporosis, premature birth, psychosocial dwarfism, stress-induced fever, ulcer, diarrhea, post-operative ileus and colonic hypersensitivity associated with psychopathological disturbance and stress.
The mechanisms and sites of action through which the standard anxiolytics and antidepressants produce their therapeutic effects remain to be elucidated. It has been hypothesized however, that they are involved in the suppression of the CRF hypersecretion that is observed in these disorders. Of particular interest is that preliminary studies examining the effects of a CRF receptor antagonist (a-helical CRF9-41) in a variety of behavioral paradigms have demonstrated that the CRF antagonist produces xe2x80x9canxiolytic-likexe2x80x9d effects qualitatively similar to the benzodiazepines [for review see G. F. Koob and K. T. Britton, In: Corticotropin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide, E. B. De Souza and C. B. Nemeroff eds., CRC Press p221 (1990)].
DuPont Merck PCT application US94/11050 describes corticotropin releasing factor antagonist compounds of the formula: 
and their use to treat psychiatric disorders and neurological diseases. Included in the description are fused pyridines and pyrimidines of the formula: 
where: V is CR1a or N; Z is CR2 or N; A is CR3O or N; and D is CR28 or N.
Other compounds reported to have activity as corticotropin releasing factors are disclosed in WO 95/33750, WO 95/34563 and WO 95/33727.
In accordance with one aspect, the present invention provides novel compounds which bind to corticotropin releasing factor receptors, thereby altering the anxiogenic effects of CRF secretion. The compounds of the present invention are useful for the treatment of psychiatric disorders and neurological diseases, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy and feeding disorders as well as treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress in mammals.
According to another aspect, the present invention provides novel compounds of formula (I) (described below) which are useful as antagonists of the corticotropin releasing factor. The compounds of the present invention exhibit activity as corticotropin releasing factor antagonists and appear to suppress CRF hypersecretion. The present invention also includes pharmaceutical compositions containing such compounds of formula (I), and methods of using such compounds for the suppression of CRF hypersecretion, and/or for the treatment of anxiogenic disorders.
According to yet another aspect, the present invention provides novel compounds, pharmaceutical compositions and methods which may be used in the treatment of affective disorder, anxiety, depression, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer""s disease, gastrointestinal disease, anorexia nervosa or other feeding disorder, drug or alcohol withdrawal symptoms, drug addiction, inflammatory disorder, fertility problems, disorders, the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, or a disorder selected from inflammatory disorders such as rheumatoid arthritis and osteoarthritis, pain, asthma, psoriasis and allergies; generalized anxiety disorder; panic, phobias, obsessive-compulsive disorder; post-traumatic stress disorder; sleep disorders induced by stress; pain perception such as fibromyalgia; mood disorders such as depression, including major depression, single episode depression, recurrent depression, child abuse induced depression, and postpartum depression; dysthemia; bipolar disorders; cyclothymia; fatigue syndrome; stress-induced headache; cancer, human immunodeficiency virus (HIV) infections; neurodegenerative diseases such as Alzheimer""s disease, Parkinson""s disease and Huntington""s disease; gastrointestinal diseases such as ulcers, irritable bowel syndrome, Crohn""s disease, spastic colon, diarrhea, and post operative ilius and colonic hypersensitivity associated by psychopathological disturbances or stress; eating disorders such as anorexia and bulimia nervosa; hemorrhagic stress; stress-induced psychotic episodes; euthyroid sick syndrome; syndrome of inappropriate antidiarrhetic hormone (ADH); obesity; infertility; head traumas; spinal cord trauma; ischemic neuronal damage (e.g., cerebral ischemia such as cerebral hippocampal ischemia); excitotoxic neuronal damage; epilepsy; cardiovascular and hear related disorders including hypertension, tachycardia and congestive heart failure; stroke; immune dysfunctions including stress induced immune dysfunctions (e.g., stress induced fevers, porcine stress syndrome, bovine shipping fever, equine paroxysmal fibrillation, and dysfunctions induced by confinement in chickens, sheering stress in sheep or human-animal interaction related stress in dogs); muscular spasms; urinary incontinence; senile dementia of the Alzheimer""s type; multiinfarct dementia; amyotrophic lateral sclerosis; chemical dependencies and addictions (e.g., dependencies on alcohol, cocaine, heroin, benzodiazepines, or other drugs); drug and alcohol withdrawal symptoms; osteoporosis; psychosocial dwarfism and hypoglycemia in mammals.
According to a still further aspect of the invention, the compounds provided by this invention (and especially labelled compounds of this invention) are also useful as standards and reagents in determining the ability of a potential pharmaceutical to bind to the CRF receptor.
[1] Thus, in a first embodiment, the present invention provides a novel compound of formula I: 
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:
A is N or Cxe2x80x94R7;
B is N or Cxe2x80x94R8;
provided that at least one of the groups A and B is N;
D is an aryl or heteroaryl group attached through an unsaturated carbon atom;
X is selected from the group CHxe2x80x94R9, Nxe2x80x94R10, O, S(O)n and a bond;
n is 0, 1 or 2;
R1 is selected from the group C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-8 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, C1-4 alkoxy-C1-4 alkyl, xe2x80x94SO2xe2x80x94C1-10 alkyl, xe2x80x94SO2xe2x80x94R1a, and xe2x80x94SO2xe2x80x94R1b;
R1 is substituted with 0-1 substituents selected from the group xe2x80x94CN, xe2x80x94S(O)nR14b, COR13a, xe2x80x94CO2R13a, xe2x80x94NR15aCOR13a, xe2x80x94N(COR13a)2, xe2x80x94NR15aCONR13aR16a, xe2x80x94NR15aCO2R14b, xe2x80x94CONR13aR16a, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, and C3-8 cycloalkyl, wherein 0-1 carbon atoms in the C4-8 cycloalkyl is replaced by a group selected from the group xe2x80x94Oxe2x80x94, xe2x80x94S(O)nxe2x80x94, xe2x80x94NR13axe2x80x94, xe2x80x94NCO2R14bxe2x80x94, xe2x80x94NCOR14bxe2x80x94 and xe2x80x94NSO2R14bxe2x80x94, and wherein N4 in 1-piperazinyl is substituted with 0-1 substituents selected from the group R13a, CO2R14b, COR14b and SO2R14b;
R1 is also substituted with 0-3 substituents independently selected at each occurrence from the group R1a, R1b, R1c, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94OR13a, xe2x80x94NR13aR16a, C1-4 alkoxy-C1-4 alkyl, and C3-8 cycloalkyl which is substituted with 0-1 R9 and in which 0-1 carbons of C4-8 cycloalkyl is replaced by xe2x80x94Oxe2x80x94;
provided that R1 is other than:
(a) a cyclohexyl-(CH2)2xe2x80x94 group;
(b) a 3-cyclopropyl-3-methoxypropyl group;
(c) an unsubstituted-(alkoxy)methyl group; and,
(d) a 1-hydroxyalkyl group;
also provided that when R1 alkyl substituted with OH, then the carbon adjacent to the ring N is other than CH2;
R1a is aryl and is selected from the group phenyl, naphthyl, indanyl and indenyl, each R1a being substituted with 0-1 xe2x80x94OR17 and 0-5 substituents independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94CN, nitro, SH, xe2x80x94S(O)nR18, xe2x80x94COR17, xe2x80x94OC(O)R18, xe2x80x94NR15aCOR17, xe2x80x94N(COR17)2, xe2x80x94NR15aCONR17aR19a, xe2x80x94NR15aCO2R18, xe2x80x94NR17aR19a, and xe2x80x94CONR17aR19a;
R1b is heteroaryl and is selected from the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-onyl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94CN, nitro, xe2x80x94OR17, SH, xe2x80x94S(O)mR18, xe2x80x94COR17, xe2x80x94OC(O)R18, xe2x80x94NR15aCOR17, xe2x80x94N(COR17)2, xe2x80x94NR15aCONR17aR19a, xe2x80x94NR15aCO2R18, xe2x80x94NR17aR19a, and xe2x80x94CONR17aR19a and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R15a, CO2R14b, COR14b and SO2R14b;
R1c is heterocyclyl and is a saturated or partially saturated heteroaryl, each heterocyclyl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94CN, nitro, xe2x80x94OR13a, SH, xe2x80x94S(O)nR14a, xe2x80x94COR13a, xe2x80x94OC(O)R14b, xe2x80x94NR15aCOR13a, xe2x80x94N(COR13a)2, xe2x80x94NR15aCONR13aR16a, xe2x80x94NR15aCO2R14b, xe2x80x94NR13aR16a, and xe2x80x94CONR13aR16a and each heterocyclyl being substituted on any nitrogen atom with 0-1 substituents selected from the group R13a, CO2R14b, COR14b and SO2R14b and wherein any sulfur atom is optionally monooxidized or dioxidized;
provided that R1 is other than a xe2x80x94(CH2)1-4-aryl, xe2x80x94(CH2)1-4-heteroaryl, or xe2x80x94(CH2)1-4-heterocycle, wherein the aryl, heteroaryl, or heterocycle group is substituted or unsubstituted;
R2 is selected from the group C1-4 alkyl, C3-8 cycloalkyl, C2-4 alkenyl, and C2-4 alkynyl and is substituted with 0-3 substituents selected from the group xe2x80x94CN, hydroxy, halo and C1-4 alkoxy;
alternatively R2, in the case where X is a bond, is selected from the group xe2x80x94CN, CF3 and C2F5;
R3, R7 and R8 are independently selected at each occurrence from the group H, Br, Cl, F, I, xe2x80x94CN, C1-4 alkyl, C3-8 cycloalkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylsulfinyl, C1-4 alkylsulfonyl, amino, C1-4 alkylamino, (C1-4 alkyl)2amino and phenyl, each phenyl is substituted with 0-3 groups selected from the group C1-7 alkyl, C3-8 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, nitro, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 alkylthio, C1-4 alkyl sulfinyl, C1-4 alkylsulfonyl, C1-6 alkylamino and (C1-4 alkyl)2amino;
provided that when R1 is unsubstituted C1-10 alkyl, then R3 is other than substituted or unsubstituted phenyl;
R9 and R10 are independently selected at each occurrence from the group H, C1-4 alkyl, C3-6 cycloalkyl-C1-4 alkyl and C3-8 cycloalkyl;
R13 is selected from the group H, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, aryl, aryl(C1-4 alkyl)-, heteroaryl and heteroaryl(C1-4 alkyl)-;
R13a and R16a are independently selected at each occurrence from the group H, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-C1-6 alkyl;
R14 is selected from the group C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, aryl, aryl(C1-4 alkyl)-, heteroaryl and heteroaryl(C1-4 alkyl)- and benzyl, each benzyl being substituted on the aryl moiety with 0-1 substituents selected from the group C1-4 alkyl, Br, Cl, F, I, C1-4 haloalkyl, nitro, C1-4 alkoxy C1-4 haloalkoxy, and dimethylamino;
R14a is selected from the group C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl and benzyl, each benzyl being substituted on the aryl moiety with 0-1 substituents selected from the group C1-4 alkyl, Br, Cl, F, I, C1-4 haloalkyl, nitro, C1-4 alkoxy, C1-4 haloalkoxy, and dimethylamino;
R14b is selected from the group C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-C1-6 alkyl;
R15 is independently selected at each occurrence from the group H, C1-4 alkyl, C3-7 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, phenyl and benzyl, each phenyl or benzyl being substituted on the aryl moiety with 0-3 groups chosen from the group C1-4 alkyl, Br, Cl, F, I, C1-4 haloalkyl, nitro, C1-4 alkoxy, C1-4 haloalkoxy, and dimethylamino;
R15a is independently selected at each occurrence from the group H, C1-4 alkyl, C3-7 cycloalkyl, and C3-6 cycloalkyl-C1-6 alkyl;
R17 is selected at each occurrence from the group H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, C1-2 alkoxy-C1-2 alkyl, C1-4 haloalkyl, R14S(O)nxe2x80x94C1-4 alkyl, and R17bR19bNxe2x80x94C2-4 alkyl;
R18 and R19 are independently selected at each occurrence from the group H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, C1-2 alkoxy-C1-2 alkyl, and C1-4 haloalkyl;
alternatively, if an NR17R19 moiety, R17 and R19 taken together form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N4 in 1-piperazinyl is substituted with 0-1 substituents selected from the group R13, CO2R14, COR14 and SO2R14;
alternatively, in an NR17bR19b moiety, R17b and R19b taken together form 1-pyrrolidinyl 1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N4 in 1-piperazinyl is substituted with 0-1 substituents selected from the group R13, CO2R14, COR14 and SO2R14;
R17a and R19a are independently selected at each occurrence from the group H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl and C1-4 haloalkyl;
aryl is independently selected at each occurrence from the group phenyl, naphthyl, indanyl and indenyl, each aryl being substituted with 0-5 substituents independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, methylenedioxy, C1-4 alkoxy-C1-4 alkoxy, xe2x80x94OR17, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94CN, xe2x80x94NO2, SH, xe2x80x94S(O)nR18, xe2x80x94COR17, xe2x80x94CO2R17, xe2x80x94OC(O)R18, xe2x80x94NR15COR17, xe2x80x94N(COR17)2, xe2x80x94NR15CONR17R19, xe2x80x94NR15CO2R18, xe2x80x94NR17R19, and xe2x80x94CONR17R19 and up to 1 phenyl, each phenyl substituent being substituted with 0-4 substituents selected from the group C1-3 alkyl, C1-3 alkoxy, Br, Cl, F, I, xe2x80x94CN, dimethylamino, CF3, C2F5, OCF3, SO2Me and acetyl;
heteroaryl is independently selected at each occurrence from the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-on-yl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94CN, nitro, xe2x80x94OR17, SH, xe2x80x94S(O)mR18, xe2x80x94COR17, xe2x80x94CO2R17, xe2x80x94OC(O)R18, xe2x80x94NR15COR17, xe2x80x94N(COR17)2, xe2x80x94NR15CONR17R19, xe2x80x94NR15CO2R18, xe2x80x94NR17R19, and xe2x80x94CONR17R19 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R15, CO2R14a, COR14a and SO2R14a; and,
provided that when D is imidazole or triazole, R1 is other than unsubstituted C1-6 linear or branched alkyl or C3-6 cycloalkyl.
[2] In a preferred embodiment, the present invention provides a novel compound of formula Ia: 
[2a] In a more preferred embodiment, the present invention provides a novel compound of formula Ia, wherein:
X is selected from the group O, S(O)n and a bond;
n is 0, 1 or 2;
R1 is selected from the group C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-8 cycloalkyl;
R1 is substituted with 0-1 substituents selected from the group xe2x80x94CN, xe2x80x94S(O)nR14b, xe2x80x94COR13a, xe2x80x94CO2R13a, and C3-8 cycloalkyl, wherein 0-1 carbon atoms in the C4-8 cycloalkyl is replaced by a group selected from the group xe2x80x94Oxe2x80x94, xe2x80x94S(O)nxe2x80x94, xe2x80x94NR13axe2x80x94, xe2x80x94NCO2R14bxe2x80x94, xe2x80x94NCOR14bxe2x80x94 and xe2x80x94NSO2R14bxe2x80x94;
R1 is also substituted with 0-2 substituents independently selected at each occurrence from the group R1a, R1b, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, Br, Cl, F, CF3, CF2CF3, xe2x80x94OR13a, xe2x80x94NR13aR16a, C1-2 alkoxy-C1-2 alkyl, and C3-8 cycloalkyl which is substituted with 0-1 R9 and in which 0-1 carbons of C4-8 cycloalkyl is replaced by xe2x80x94Oxe2x80x94;
provided that R1 is other than a cyclohexyl-(CH2)2xe2x80x94 group;
R1a is aryl and is selected from the group phenyl and indanyl, each R1a being substituted with 0-1 xe2x80x94OR17 and 0-5 substituents independently selected at each occurrence from the group C1-4 alkyl, C3-6 cycloalkyl, Br, Cl, F, C1-4 haloalkyl, xe2x80x94CN, xe2x80x94S(O)nR18, xe2x80x94COR17, xe2x80x94NR17aR19a, and xe2x80x94CONR17aR19a;
R1b is heteroaryl and is selected from the group pyridyl, pyrimidinyl, furanyl, thienyl, imidazolyl, thiazolyl, pyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, and indazolyl, each heteroaryl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-4 alkyl, C3-6 cycloalkyl, Br, Cl, F, CF3, xe2x80x94CN, xe2x80x94OR17, xe2x80x94S(O)mR18, xe2x80x94COR17, xe2x80x94NR17aR19a, and xe2x80x94CONR17aR19a and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R15a, CO2R14b, COR14b and SO2R14b;
provided that R1 is other than a xe2x80x94(CH2)1-4-aryl or xe2x80x94(CH2)1-4-heteroaryl wherein the aryl or heteroaryl group is substituted or unsubstituted;
R2 is selected from the group C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl and is substituted with 0-1 substituents selected from the group xe2x80x94CN, OH, Cl, F, and C1-4 alkoxy;
R3 and R8 are independently selected at each occurrence from the group H, Br, Cl, F, xe2x80x94CN, C1-4 alkyl, C3-6 cycloalkyl, C1-4 alkoxy, NH2, C1-4 alkylamino, and (C1-4 alkyl)2-amino;
R9 is independently selected at each occurrence from the group H, C1-4 alkyl and C3-8 cycloalkyl;
R13 is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, C3-6 cycloalkyl-C1-2 alkyl, aryl(C1-2 alkyl)-, and heteroaryl(C1-2 alkyl)-;
R13a and R16a are independently selected at each occurrence from the group H, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-C1-6 alkyl;
R14a is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, C3-6 cycloalkyl-C1-2 alkyl, aryl(C1-2 alkyl)-, and heteroaryl(C1-2 alkyl)-;
R14a is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, and C3-6 cycloalkyl-C1-2 alkyl;
R14b is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-C1-2 alkyl;
R15 is independently selected at each occurrence from the group H, C1-4 alkyl, C3-7 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, phenyl and benzyl, each phenyl or benzyl being substituted on the aryl moiety with 0-3 groups chosen from the group C1-4 alkyl, Br, Cl, F, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and dimethylamino;
R15a is independently selected at each occurrence from the group H, C1-4 alkyl, C3-7 cycloalkyl, and C3-6 cycloalkyl-C1-6 alkyl;
R17, R18 and R19 are independently selected at each occurrence from the group H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, C1-2 alkoxy-C1-2 alkyl, and C1-4 haloalkyl;
alternatively, in an NR17R19 moiety, R17 and R19 taken together form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N4 in 1-piperazinyl is substituted with 0-1 substituents selected from the group R13, CO2R14, COR14 and SO2R14;
R17a and R19a are independently selected at each occurrence from the group H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl and C1-4 haloalkyl;
aryl is phenyl substituted with 1-4 substituents independently selected at each occurrence from the group C1-4 alkyl, C3-6 cycloalkyl, xe2x80x94OR17, Br, Cl, F, C1-4 haloalkyl, xe2x80x94CN, xe2x80x94S(O)nR18, xe2x80x94COR17, xe2x80x94CO2R17, xe2x80x94NR15COR17, xe2x80x94NR15CO2R18, xe2x80x94NR17R19, and xe2x80x94CONR17R19; and,
heteroaryl is independently selected at each occurrence from the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-on-yl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted 1-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, C1-4 haloalkyl, xe2x80x94CN, xe2x80x94OR17, xe2x80x94S(O)mR18, xe2x80x94COR17, xe2x80x94CO2R17, xe2x80x94OC(O)R18, xe2x80x94NR15COR17, xe2x80x94N(COR17)2, xe2x80x94NR15CO2R18, xe2x80x94NR17R19, and xe2x80x94CONR17R19 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R15, CO2R14a, COR14a and SO2R14a.
[2b] In an even more preferred embodiment, the present invention provides a novel compound of formula Ia, wherein:
X is selected from the group O, S and a bond;
R1 is substituted C1-6 alkyl;
R1 is substituted with 0-1 substituents selected from the group xe2x80x94CN, xe2x80x94CO2R13a, and C3-8 cycloalkyl, wherein 0-1 carbon atoms in the C4-8 cycloalkyl is replaced by a group selected from the group xe2x80x94Oxe2x80x94, xe2x80x94S(O)nxe2x80x94, and xe2x80x94NR13axe2x80x94;
R1 is also substituted with 0-2 substituents independently selected at each occurrence from the group R1a, R1b, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, Br, Cl, F, CF3, xe2x80x94OR13a, xe2x80x94NR13aR16a, C1-2 alkoxy-C1-2 alkyl, and C3-6 cycloalkyl which is substituted with 0-1 CH3 and in which 0-1 carbons of C4-8 cycloalkyl is replaced by xe2x80x94Oxe2x80x94;
provided that R1 is other than a cyclohexyl-(CH2)2xe2x80x94 group;
R1a is aryl and is phenyl substituted with 0-1 substituents selected from OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, and OCF3, and 0-3 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, Br, Cl, F, CF3, xe2x80x94CN, SCH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2;
R1b is heteroaryl and is selected from the group furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, and indazolyl, each heteroaryl being substituted on 0-3 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH3, CO2CH3, COCH3 and SO2CH3;
provided that R1 is other than a xe2x80x94(CH2)1-4-aryl or xe2x80x94(CH2)1-4-heteroaryl wherein the aryl or heteroaryl group is substituted or unsubstituted;
R2 is selected from the group CH3, CH2CH3, CH(CH3)2, and CH2CH2CH3;
R3 and R8 are independently selected at each occurrence from the group H, CH3, CH2CH3, CH(CH3)2, and CH2CH2CH3;
aryl is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, SO2CH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2; and,
heteroaryl is independently selected at each occurrence from the group pyridyl, indolyl, benzothienyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, and benzoxazolin-2-on-yl, each heteroaryl being substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, SO2CH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH3, CO2CH3, COCH3 and SO2CH3.
[2c] In a still more preferred embodiment, the present invention provides a novel compound of formula Ia, wherein:
R1 is substituted C1;
R1 is substituted with 0-1 substituents selected from the group xe2x80x94CN, xe2x80x94CO2CH3, and xe2x80x94CO2CH2CH3;
R1 is also substituted with 0-2 substituents independently selected at each occurrence from the group R1a, R1b, CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, xe2x80x94(CH2)3CH3, xe2x80x94CHxe2x95x90CH2, xe2x80x94CHxe2x95x90CH(CH3), xe2x80x94CHxe2x89xa1CH, xe2x80x94CHxe2x89xa1C(CH3), xe2x80x94CH2OCH3, xe2x80x94CH2CH2OCH3, F, CF3, cyclopropyl, CH3-cyclopropyl, cyclobutyl, CH3-cyclobutyl, cyclopentyl, CH3-cyclopentyl;
R1a is phenyl substituted with 0-1 substituents selected from OCH3, OCH2CH3, and OCF3, and 0-2 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, Br, Cl, F, CF3, xe2x80x94CN, and SCH3;
R1b is heteroaryl and is selected from the group furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, and tetrazolyl, each heteroaryl being substituted on 0-3 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, OCH3, OCH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, and SCH3 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH3, CO2CH3, COCH3 and SO2CH3;
provided that R1 is other than a xe2x80x94(CH2)1-4-aryl or xe2x80x94(CH2)1-4-heteroaryl wherein the aryl or heteroaryl group is substituted or unsubstituted;
R2 is selected from the group CH3, CH2CH3, and CH(CH3)2;
R3 and R8 are independently selected at each occurrence from the group H and CH3;
aryl is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, SO2CH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2; and,
heteroaryl is pyridyl substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, SO2CH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2.
[2d] In a further preferred embodiment, the present invention provides a novel compound of formula Ia, wherein:
R1 is substituted (cyclopropyl)-C1 alkyl or (cyclobutyl)-C1 alkyl;
R1 is substituted with 0-1 xe2x80x94CN;
R1 is also substituted with 0-1 substituents independently selected at each occurrence from the group R1a, R1b, CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, xe2x80x94(CH2)3CH3, xe2x80x94CHxe2x95x90CH2, xe2x80x94CHxe2x95x90CH(CH3), xe2x80x94CHxe2x89xa1CH, xe2x80x94CHxe2x89xa1C(CH3), xe2x80x94CH2OCH3, xe2x80x94CH2CH2OCH3, F, CF3, cyclopropyl, and CH3-cyclopropyl;
R1a is phenyl substituted with 0-1 substituents selected from OCH3, OCH2CH3, and OCF3, and 0-2 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, Br, Cl, F, CF3, xe2x80x94CN, and SCH3;
R1b is heteroaryl and is selected from the group furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, and pyrazolyl, each heteroaryl being substituted on 0-3 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, OCH3, OCH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, and SCH3.
[2e] In another further preferred embodiment, the present invention provides a novel compound of formula Ia, wherein:
R1 is (cyclopropyl)C1 alkyl or (cyclobutyl)-C1 alkyl substituted with 1 substituent independently selected at each occurrence from the group R1a, R1b, CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, xe2x80x94(CH2)3CH3, xe2x80x94CHxe2x95x90CH2, xe2x80x94CHxe2x95x90CH(CH3), xe2x80x94CHxe2x89xa1CH, xe2x80x94CHxe2x89xa1C(CH3), xe2x80x94CH2OCH3, xe2x80x94CH2CH2OCH3, F, CF3, cyclopropyl, and CH3-cyclopropyl;
R1a is phenyl substituted with 0-2 substituents independently selected at each occurrence from the group CH3, CH2CH3, Cl, F, and CF3;
R1b is heteroaryl and is selected from the group furanyl, thienyl, and isoxazolyl, each heteroaryl being substituted on 0-2 carbon atoms with a substituent independently selected at each occurrence from the group CH3, OCH3, Cl, F, and CF3.
[2f] In an even further preferred embodiment, the present invention provides a novel compound of formula Ia, wherein:
R1 is selected from the group (cyclopropyl)CHxe2x80x94CH3, (cyclopropyl)CHxe2x80x94CH2CH3, (cyclopropyl)CHxe2x80x94CH2OCH3, (cyclopropyl)CHxe2x80x94CH2CH2CH3, (cyclopropyl)CHxe2x80x94CH2CH2OCH3, (cyclopropyl)2CH, phenyl(cyclopropyl)CH, furanyl(cyclopropyl)CH, thienyl(cyclopropyl)CH, isoxazolyl(cyclopropyl)CH, (CH3-furanyl)(cyclopropyl)CH, (cyclobutyl)CHxe2x80x94CH3, (cyclobutyl)CHxe2x80x94CH2CH3, (cyclobutyl)CHxe2x80x94CH2OCH3, (cyclobutyl)CHxe2x80x94CH2CH2CH3, (cyclobultyl)CHxe2x80x94CH2CH2OCH3, (cyclobutyl)2CH, phenyl(cyclobutyl)CH, furanyl(cyclobutyl)CH, thienyl(cyclobutyl)CH, isoxazolyl(cyclobutyl)CH, and (CH3-furanyl)(cyclobutyl)CH;
[2g] In another further preferred embodiment, the present invention provides a novel compound of formula Ia, wherein:
D is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, and CF3.
[2h] In another further preferred embodiment, the present invention provides a novel compound of formula Ia, wherein:
D is pyridyl substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, and CF3.
[2i] In another preferred embodiment, the present invention provides a novel compound of formula Ia, wherein the compound is selected from the group:
3-(1-cyclopropylpropyl)-7-(2,4-dichlorophenyl)-2-ethyl-3H-imidazo[4,5-b]pyridine;
3-(1-cyclopropylpropyl)-7-(2,4-dichlorophenyl)-2-methoxy-3H-imidazo[4,5-b]pyridine;
3-(1-cyclopropylpropyl)-7-(2,4-dichlorophenyl)-2-(methylsulfanyl)-3H-imidazo[4,5-b]pyridine;
7-[2-chloro-4-(trifluoromethyl)phenyl]-3-(1-cyclopropylpropyl)-2-ethyl-3H-imidazo[4,5-b]pyridine;
7-[2-chloro-4-(trifluoromethyl)phenyl]-3-(1-cyclopropylpropyl)-2-methoxy-3H-imidazo[4,5-b]pyridine;
7-[2-chloro-4-(trifluoromethyl)phenyl]-3-(1-cyclopropylpropyl)-2-(methylsulfanyl)-3H-imidazo[4,5-b]pyridine;
3-(1-cyclopropylpropyl)-2-ethyl-7-[2-methyl-4-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine;
7-(2-chloro-4-methoxyphenyl)-3-(1-cyclopropylpropyl)-2-ethyl-3H-imidazo[4,5-b]pyridine;
7-(2-chloro-4-methoxyphenyl)-3-(1-cyclopropylpropyl)-2-methoxy-3H-imidazo[4,5-b]pyridine;
3-(1-cyclopropylpropyl)-2-ethyl-7-(4-methoxy-2,5-dimethylphenyl)-3H-imidazo[4,5-b]pyridine;
3-(1-cyclopropylpropyl)-2-methoxy-7-(4-methoxy-2,5-dimethylphenyl)-3H-imidazo[4,5-b]pyridine;
7-(2-chloro-4-methoxyphenyl)-3-(1-cyclopropylpropyl)-2-ethyl-3H-imidazo[4,5-b]pyridine;
7-(2-chloro-4-methoxyphenyl)-3-(1-cyclopropylpropyl)-2-methoxy-3H-imidazo[4,5-b]pyridine;
7-(2-chloro-5-fluoro-4-methoxyphenyl)-3-(1-cyclopropylpropyl)-2-ethyl-3H-imidazo[4,5-b]pyridine;
7-(2-chloro-fluoro-4-methoxyphenyl)-3-(1-cyclopropylpropyl)-2-methoxy-3H-imidazo[4,5-b]pyridine;
7-(2-chloro-5-fluoro-4-methylphenyl)-3-(1-cyclopropylpropyl)-2-ethyl-3H-imidazo[4,5-b]pyridine;
7-(2-chloro-fluoro-4-methylphenyl)-3-(1-cyclopropylpropyl)-2-methoxy-3H-imidazo[4,5-b]pyridine;
3-(1-cyclopropylpropyl)-2-ethyl-7-(2,4,5-trimethylphenyl)-3H-imidazo[4,5-b]pyridine;
3-(1-cyclopropylpropyl)-2-methoxy-7-(2,4,5-trimethylphenyl)-3H-imidazo[4,5-b]pyridine;
3-(1-cyclopropylpropyl)-2-ethyl-7-(2,5,6-trimethyl-3-pyridinyl)-3H-imidazo[4,5-b]pyridine;
3-(1-cyclopropylpropyl)-2-methoxy-7-(2,5,6-trimethyl-3-pyridinyl)-3H-imidazo[4,5-b]pyridine;
3-(1-cyclopropylpropyl)-7-(2,6-dimethyl-3-pyridinyl)-2-ethyl-3H-imidazo[4,5-b]pyridine;
3-(1-cyclopropylpropyl)-7-(2,6-dimethyl-3-pyridinyl)-2-methoxy-3H-imidazo[4,5-b]pyridine;
3-(1-cyclopropylpropyl)-7-(2,6-dimethoxy-3-pyridinyl)-2-ethyl-3H-imidazo[4,5-b]pyridine;
7-(2,4-dichlorophenyl)-2-ethyl-3-(1-ethylpropyl)-3H-imidazo[4,5-b]pyridine;
7-(2,4-dichlorophenyl)-3-(1-ethylpropyl)-2-methoxy-3H-imidazo[4,5-b]pyridine;
7-[2-chloro-4-(trifluoromethyl)phenyl]-2-ethyl-3-(1-ethylpropyl)-3H-imidazo[4,5-b pyridine;
5 7-[2-chloro-4-(trifluoromethyl)phenyl]-3-(1-ethylpropyl)-2-methoxy-3H-imidazo[4,5-b]pyridine;
7-[2-chloro-4-(methylsulfonyl)phenyl]-2-ethyl-3-(1-ethylpropyl)-3H-imidazo[4,5-b]pyridine;
7-[2-chloro-4-(methylsulfonyl)phenyl]-3-(1-ethylpropyl)-2-methoxy-3H-imidazo[4,5-b]pyridine;
2-ethyl-3-(1-ethylpropyl)-7-(4-methoxy-2,5-dimethylphenyl)-3H-imidazo[4,5-b]pyridine;
3-(1-ethylpropyl)-2-methoxy-7-(4-methoxy-2,5-dimethylphenyl)-3H-imidazo[4,5-b]pyridine;
7-(2-chloro-4-methoxyphenyl)-2-ethyl-3-(1-ethylpropyl)-3H-imidazo[4,5-b]pyridine;
7-(2-chloro-4-methoxyphenyl)-3-(1-ethylpropyl)-2-methoxy-3H-imidazo[4,5-b]pyridine;
2-ethyl-3-(1-ethylpropyl)-7-[4-methoxy-2-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine;
3-(1-ethylpropyl)-2-methoxy-7-[4-methoxy-2-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine;
7-(2,6-dimethoxy-3-pyridinyl)-2-ethyl-3-(1-ethylpropyl)-3H-imidazo[4,5-b]pyridine;
7-(2,6-dimethyl-3-pyridinyl)-2-ethyl-3-(1-ethylpropyl)-3H-imidazo[4,5-b]pyridine;
2-ethyl-3-(1-ethylpropyl)-7-(2,5,6-trimethyl-3-pyridinyl)-3H-imidazo[4,5-b]pyridine;
2-ethyl-3-(1-ethylpropyl)-7-(5-fluoro-4-methoxy-2-methylphenyl)-3H-imidazo[4,5-b]pyridine;
3-(1-ethylpropyl)-7-(5-fluoro-4-methoxy-2-methylphenyl)-2-methoxy-3H-imidazo[4,5-b]pyridine;
3-chloro-4-[2-ethyl-3-(1-ethylpropyl)-3H-imidazo[4,5-b]pyridin-7-yl]benzonitrile;
3-chloro-4-[3-(1-ethylpropyl)-2-methoxy-3H-imidazo[4,5-b]pyridin-7-yl]benzonitrile;
1-{3-chloro-4-[2-ethyl-3-(1-ethylpropyl)-3H-imidazo[4,5-b]pyridin-7-yl]phenyl}-1-ethanone;
1-{3-chloro-4-(3-(1-ethylpropyl)-2-methoxy-3H-imidazo[4,5-b]pyridin-7-yl]phenyl}-1-ethanone;
3-(dicyclopropylmethyl)-2-ethyl-7-(5-fluoro-4-methoxy-2-methylphenyl)-3H-imidazo[4,5-b]pyridine;
3-(dicyclopropylmethyl)-7-(5-fluoro-4-methoxy-2-methylphenyl)-2-methoxy-3H-imidazo[4,5-b]pyridine;
7-(2-chloro-4-methoxyphenyl)-3-(dicyclopropylmethyl)-2-ethyl-3H-imidazo[4,5-b]pyridine;
7-(2-chloro-4-methoxyphenyl)-3-(dicyclopropylmethyl)-2-methoxy-3H-imidazo[4,5-b]pyridine;
7-(2,4-dichlorophenyl)-3-(dicyclopropylmethyl)-2-ethyl-3H-imidazo[4,5-b]pyridine;
7-(2,4-dichlorophenyl)-3-(dicyclopropylmethyl)-2-methoxy-3H-imidazo[4,5-b]pyridine;
7-[2-chloro-4-(trifluoromethyl)phenyl]-3-(dicyclopropylmethyl)-2-ethyl-3H-imidazo[4,5-b]pyridine;
7-[2-chloro-4-(trifluoromethyl)phenyl]-3-(dicyclopropylmethyl)-2-methoxy-3H-imidazo[4,5-b]pyridine;
7-(2,4-dichlorophenyl)-2-ethyl-3-(1-ethyl-3-methoxypropyl)-3H-imidazo[4,5-b]pyridine;
7-(2,4-dichlorophenyl)-3-(1-ethyl-3-methoxypropyl)-2-methoxy-3H-imidazo[4,5-b]pyridine;
7-[2-chloro-4-(trifluoromethyl)phenyl]-2-ethyl-3-(1-ethyl-3-methoxypropyl)-3H-imidazo[4,5-b]pyridine;
7-[2-chloro-4-(trifluoromethyl)phenyl]-3-(1-ethyl-3-methoxypropyl)-2-methoxy-3H-imidazo[4,5-b]pyridine;
7-(2-chloro-4-methoxyphenyl)-2-ethyl-3-(1-ethyl-3-methoxypropyl)-3H-imidazo[4,5-b]pyridine;
7-(2-chloro-4-methoxyphenyl)-3-(1-ethyl-3-methoxypropyl)-2-methoxy-3H-imidazo[4,5-b]pyridine;
7-(2-chloro-5-fluoro-4-methoxyphenyl)-2-ethyl-3-(1-ethyl-3-methoxypropyl)-3H-imidazo[4,5-b]pyridine;
7-(2-chloro-5-fluoro-4-methoxyphenyl)-3-(1-ethyl-3-methoxypropyl)-2-methoxy-3H-imidazo[4,5-b]pyridine;
2-ethyl-3-(1-ethyl-3-methoxypropyl)-7-(4-methoxy-2,5-dimethylphenyl)-3H-imidazo[4,5-b]pyridine;
3-(1-ethyl-3-methoxypropyl)-2-methoxy-7-(4-methoxy-2,5-dimethylphenyl)-3H-imidazo[4,5-b]pyridine;
2-ethyl-3-(1-ethyl-3-methoxypropyl)-7-(5-fluoro-4-methoxy-2-methylphenyl)-3H-imidazo[4,5-b]pyridine;
3-(1-ethyl-3-methoxypropyl)-7-(5-fluoro-4-methoxy-2-methylphenyl)-2-methoxy-3H-imidazo[4,5-b]pyridine;
7-(2-chloro-5-fluoro-4-methylphenl)-2-ethyl-3-(1-ethyl-3-methoxypropyl)-3H-imidazo[4,5-b]pyridine;
7-(2-chloro-5-fluoro-4-methylphenyl)-3-(1-ethyl-3-methoxypropyl)-2-methoxy-3H-imidazo[4,5-b]pyridine;
7-[2-chloro-4-(methylsulfonyl)phenyl]-2-ethyl-3-(1-ethyl-3-methoxypropyl)-3H-imidazo[4,5-b]pyridine;
7-[2-chloro-4-(methylsulfonyl)phenyl]-3-(1-ethyl-3-methoxypropyl)-2-methoxy-3H-imidazo[4,5-b]pyridine;
1-{3-chloro-4-[2-ethyl-3-(1-ethyl-3-methoxypropyl)-3H-imidazo[4,5-b]pyridin-7-yl]phenyl}-1-ethanone;
1-{3-chloro-4-[3-(1-ethyl-3-methoxypropyl)-2-methoxy-3H-imidazo[4,5-b]pyridin-7-yl]phenyl}-1-ethanone;
1-{5-[2-ethyl-3-(1-ethyl-3-methoxypropyl)-3H-imidazo[4,5-b]pyridin-7-yl]-6-methyl-2-pyridinyl}-1-ethanone;
1-{5-[3-(1-ethyl-3-methoxypropyl)-2-methoxy-3H-imidazo[4,5-b]pyridin-7-yl]-6-methyl-2-pyridinyl}-1-ethanone;
2-ethyl-3-(1-ethyl-3-methoxypropyl)-7-(6-methoxy-2-methyl-3-pyridinyl)-3H-imidazo[4,5-b]pyridine;
3-(1-ethyl-3-methoxypropyl)-2-methoxy-7-(6-methoxy-2-methyl-3-pyridinyl)-3H-imidazo[4,5-b]pyridine;
7-(2,6-dimethoxy-3-pyridinyl)-2-ethyl-3-(1-ethyl-3-methoxypropyl)-3H-imidazo[4,5-b]pyridine;
7-(2,6-dimethoxy-3-pyridinyl)-3-(1-ethyl-3-methoxypropyl)-2-methoxy-3H-imidazo[4,5-b]pyridine;
7-(2,6-dimethyl-3-pyridinyl)-2-ethyl-3-(1-ethyl-3-methoxypropyl)-3H-imidazo[4,5-b]pyridine;
7-(2,6-dimethyl-3-pyridinyl)-3-(1-ethyl-3-methoxypropyl)-2-methoxy-3H-imidazo[4,5-b]pyridine;
2-ethyl-3-(1-ethyl-3-methoxypropyl)-7-(2,5,6-trimethyl-3-pyridinyl)-3H-imidazo[4,5-b]pyridine;
3-(1-ethyl-3-methoxypropyl)-2-methoxy-7-(2,5,6-trimethyl-3-pyridinyl)-3H-imidazo[4,5-b]pyridine;
7-(2,4-dichlorophenyl)-2-ethyl-3-[1-(methoxymethyl)propyl]-3H-imidazo[4,5-b]pyridine;
7-(2,4-dichlorophenyl)-2-methoxy-3-[1-(methoxymethyl)propyl]-3H-imidazo[4,5-b]pyridine;
7-[2-chloro-4-(trifluoromethyl)phenyl]-2-ethyl-3-[1-(methoxymethyl)propyl]-3H-imidazo[4,5-b]pyridine;
7-[2-chloro-4-(trifluoromethyl)phenyl]-2-methoxy-3-[1-(methoxymethyl)propyl]-3H-imidazo[4,5-b]pyridine;
7-(2-chloro-5-fluoro-4-methylphenyl)-2-ethyl-3-[1-(methoxymethyl)propyl]-3H-imidazo[4,5-b]pyridine;
7-(2-chloro-5-fluoro-4-methylphenyl)-2-methoxy-3-[1-(methoxymethyl)propyl]-3H-imidazo[4,5-b]pyridine;
2-ethyl-7-(4-methoxy-2,5-dimethylphenyl)-3-[1-(methoxymethyl)propyl]-3H-imidazo[4,5-b]pyridine;
2-methoxy-7-(4-methoxy-2,5-dimethylphenyl)-3-[1-(methoxymethyl)propyl]-3H-imidazo[4,5-b]pyridine;
2-ethyl-7-(5-fluoro-4-methoxy-2-methylphenyl)-3-[1-(methoxymethyl)propyl]-3H-imidazo[4,5-b]pyridine;
7-(5-fluoro-4-methoxy-2-methylphenyl)-2-methoxy-3-[1-(methoxymethyl)propyl]-3H-imidazo[4,5-b]pyridine;
2-ethyl-3-[1-(methoxymethyl)propyl]-7-(6-methoxy-2-methyl-3-pyridinyl)-3H-imidazo[4,5-b]pyridine;
2-methoxy-3-[1-(methoxymethyl)propyl]-7-(6-methoxy-2-methyl-3-pyridinyl)-3H-imidazo[4,5-b]pyridine;
7-(2,6-dimethoxy-3-pyridinyl)-2-ethyl-3-[1-(methoxymethyl)propyl]-3H-imidazo[4,5-b]pyridine;
7-(2,6-dimethoxy-3-pyridinyl)-2-methoxy-3-[1-(methoxymethyl)propyl]-3H-imidazo[4,5-b]pyridine;
7-(2,6-dimethyl-3-pyridinyl)-2-ethyl-3-[1-(methoxymethyl)propyl]-3H-imidazo[4,5-b]pyridine;
7-(2, 6-dimethyl-3-pyridinyl)-2-methoxy-3-[1-(methoxymethyl)propyl]-3H-imidazo[4,5-b]pyridine;
2-ethyl-3-[1-(methoxymethyl)propyl]-7-(2,5,6-trimethyl-3-pyridinyl)-3H-imidazo[4,5-b]pyridine;
2-methoxy-3-[1-(methoxymethyl)propyl]-7-(2,5,6-trimethyl-3-pyridinyl)-3H-imidazo[4,5-b]pyridine;
7-[2-chloro-4-(methylsulfonyl)phenyl]-2-ethyl-3-[1-(methoxymethyl)propyl]-3H-imidazo[4,5-b]pyridine; and
7-[2-chloro-4-(methylsulfonyl)phenyl]-2-methoxy-3-[1-(methoxymethyl)propyl]-3H-imidazo[4,5-b]pyridine;
or a pharmaceutically acceptable salt form thereof.
[2j] In another more preferred embodiment, the present invention provides a novel compound of formula Ia, wherein:
R1 is C3-8 cycloalkyl;
R1 is substituted with 0-1 substituents selected from the group xe2x80x94CN, xe2x80x94S(O)nR14b, COR13a, xe2x80x94CO2R13a, xe2x80x94NR15aCOR13a, xe2x80x94N(COR13a)2, xe2x80x94NR15aCONR13aR16a, NR15aCO2R14b, xe2x80x94CONR13aR16a, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, and C4-8 cycloalkyl, wherein 0-1 carbon atoms in the C4-8 cycloalkyl is replaced by a group selected from the group xe2x80x94Oxe2x80x94, xe2x80x94S(O)nxe2x80x94, xe2x80x94NR13axe2x80x94, xe2x80x94NCO2R14bxe2x80x94, xe2x80x94NCOR14bxe2x80x94 and xe2x80x94NSO2R14bxe2x80x94, and wherein N4 in 1-piperazinyl is substituted with 0-1 substituents selected from the group R13a, CO2R14b, COR14b and SO2R14b; and,
R1 is also substituted with 0-3 substituents independently selected at each occurrence from the group R1a, R1b, R1c, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94OR13a, C1-2 alkoxy-C1-2 alkyl, and xe2x80x94NR13aR16a.
[2k] In another even more preferred embodiment, the present invention provides a novel compound of formula Ia, wherein:
X is selected from the group O, S(O)n and a bond;
n is 0, 1 or 2;
R1 is selected from the group cyclopropyl, cyclobutyl, and cyclopentyl;
R1 is substituted with 0-1 substituents selected from the group xe2x80x94CN, xe2x80x94S(O)nR14b, xe2x80x94COR13a, xe2x80x94CO2R13a, and C4-8 cycloalkyl, wherein one carbon atom in the C4-8 cycloalkyl is replaced by a group selected from the group xe2x80x94Oxe2x80x94, xe2x80x94S(O)nxe2x80x94, xe2x80x94NR13axe2x80x94, xe2x80x94NCO2R14bxe2x80x94, xe2x80x94NCOR14bxe2x80x94 and xe2x80x94NSO2R14bxe2x80x94;
R is also substituted with 0-2 substituents independently selected at each occurrence from the group R1a, R1b, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, Br, Cl, F, CF3, CF2CF3, xe2x80x94OR13a, C1-2 alkoxy-C1-2 alkyl, and xe2x80x94NR13aR16a;
R1a is aryl and is selected from the group phenyl and indanyl, each R1a being substituted with 0-1 xe2x80x94OR17 and 0-5 substituents independently selected at each occurrence from the group C1-4 alkyl, C3-6 cycloalkyl, Br, Cl, F, C1-4 haloalkyl, xe2x80x94CN, xe2x80x94S(O)nR18, xe2x80x94COR17, xe2x80x94NR17aR19a, and xe2x80x94CONR17aR19a;
R1b is heteroaryl and is selected from the group pyridyl, pyrimidinyl, furanyl, thienyl, imidazolyl, thiazolyl, pyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, and indazolyl, each heteroaryl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-4 alkyl, C3-6 cycloalkyl, Br, Cl, F, CF3, xe2x80x94CN, xe2x80x94OR17, xe2x80x94S(O)mR18, xe2x80x94COR17, xe2x80x94NR17aR19a, and xe2x80x94CONR17aR19a and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R15a, CO2R14b, COR14b and SO2R14b;
R2 is selected from the group C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl and is substituted with 0-1 substituents selected from the group xe2x80x94CN, OH, Cl, F, and C1-4 alkoxy;
R9 is independently selected at each occurrence from the group H, C1-4 alkyl and C3-8 cycloalkyl;
R3 and R8 are independently selected at each occurrence from the group H, Br, Cl, F, xe2x80x94CN, C1-4 alkyl, C3-6 cycloalkyl, C1-4 alkoxy, NH2, C1-4 alkylamino, and (C1-4 alkyl)2-amino;
R13 is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, C3-6 cycloalkyl-C1-2 alkyl, aryl(C1-2 alkyl)-, and heteroaryl(C1-2 alkyl)-;
R13a and R16a are independently selected at each occurrence from the group H, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-C1-6 alkyl;
R14 is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, C3-6 cycloalkyl-C1-2 alkyl, aryl(C1-2 alkyl)-, and heteroaryl(C1-2 alkyl)-;
R14a is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, and C3-6 cycloalkyl-C1-2 alkyl;
R14b is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-C1-2 alkyl;
R15 is independently selected at each occurrence from the group H, C1-4 alkyl, C3-7 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, phenyl and benzyl, each phenyl or benzyl being substituted on the aryl moiety with 0-3 groups chosen from the group C1-4 alkyl, Br, Cl, F, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and dimethylamino;
R15a is independently selected at each occurrence from the group H, C1-4 alkyl, C3-7 cycloalkyl, and C3-6 cycloalkyl-C1-6 alkyl;
R17, R18 and R19 are independently selected at each occurrence from the group H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, C1-2 alkoxy-C1-2 alkyl, and C1-4 haloalkyl;
alternatively, in an NR17R19 moiety, R17 and R19 taken together form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N4 in 1-piperazinyl is substituted with 0-1 substituents selected from the group R13, CO2R14, COR14 and SO2R14;
R17a and R19a are independently selected at each occurrence from the group H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl and C1-4 haloalkyl;
aryl is phenyl substituted with 1-4 substituents independently selected at each occurrence from the group C1-4 alkyl, C3-6 cycloalkyl, xe2x80x94OR17, Br, Cl, F, C1-4 haloalkyl, xe2x80x94CN, xe2x80x94S(O)nR18, xe2x80x94COR17, xe2x80x94CO2R17, xe2x80x94NR15COR17, xe2x80x94NR15CO2R18, xe2x80x94NR17R19, and xe2x80x94CONR17R19; and,
heteroaryl is independently selected at each occurrence from the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-on-yl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted 1-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, C1-4 haloalkyl, xe2x80x94CN, xe2x80x94OR17, xe2x80x94S(O)mR18, xe2x80x94COR17, xe2x80x94CO2R17, xe2x80x94OC(O)R18, xe2x80x94NR15COR17, xe2x80x94N(COR17)2, xe2x80x94NR15CO2R18, xe2x80x94NR17R19, and xe2x80x94CONR17R19 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R15, CO2R14a, COR14a and SO2R14a.
[2l] In another still more preferred embodiment, the present invention provides a novel compound of formula Ia, wherein:
X is selected from the group O, S and a bond;
R1 is substituted with 0-1 substituents selected from the group xe2x80x94CN, xe2x80x94CO2R13a, and C4-8 cycloalkyl, wherein 0-1 carbon atoms in the C4-8 cycloalkyl is replaced by a group selected from the group xe2x80x94Oxe2x80x94, xe2x80x94S(O)nxe2x80x94, and xe2x80x94NR13axe2x80x94;
R1 is also substituted with 0-2 substituents independently selected at each occurrence from the group R1a, R1b, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, Br, Cl, F, CF3, CF3, xe2x80x94OR13a, xe2x80x94OH, xe2x80x94OCH3, xe2x80x94OCH2CH3, xe2x80x94CH2OCH3, xe2x80x94CH2CH2OCH3, and xe2x80x94NR13aR16a;
R1a is aryl and is phenyl substituted with 0-1 substituents selected from OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, and OCF3, and 0-3 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, Br, Cl, F, CF3, xe2x80x94CN, SCH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2;
R1b is heteroaryl and is selected from the group furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, and indazolyl, each heteroaryl being substituted on 0-3 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH3, CO2CH3, COCH3 and SO2CH3;
R2 is selected from the group CH3, CH2CH3, CH(CH3)2, and CH2CH2CH3;
R3 and R8 are independently selected at each occurrence from the group H, CH3, CH2CH3, CH(CH3)2, and CH2CH2CH3;
aryl is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, SO2CH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2; and,
heteroaryl is independently selected at each occurrence from the group pyridyl, indolyl, benzothienyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, and benzoxazolin-2-on-yl, each heteroaryl being substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, SO2CH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH3, CO2CH3, COCH3 and SO2CH3.
[2m] In another further preferred embodiment, the present invention provides a novel compound of formula Ia, wherein:
R1 is substituted with 0-2 substituents independently selected at each occurrence from the group R1a, R1b, CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, xe2x80x94(CH2)3CH3, xe2x80x94CHxe2x95x90CH2, xe2x80x94CHxe2x95x90CH(CH3), xe2x80x94CHxe2x89xa1CH, xe2x80x94CHxe2x89xa1C(CH3), xe2x80x94CH2OCH3, xe2x80x94CH2CH2OCH3, F, and CF3;
R1a is phenyl substituted with 0-1 substituents selected from OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, and OCF3, and 0-2 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, Br, Cl, F, CF3, xe2x80x94CN, and SCH3;
R1b is heteroaryl and is selected from the group furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, and tetrazolyl, each heteroaryl being substituted on 0-3 carbon-atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, OCH3, OCH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, and SCH3 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH3, CO2CH3, COCH3 and SO2CH3;
R2 is selected from the group CH3, CH2CH3, and CH(CH3)2;
R3 and R8 are independently selected at each occurrence from the group H and CH3;
aryl is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, SO2CH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2; and,
heteroaryl is pyridyl substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, SO2CH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2.
[2n] In another even further preferred embodiment, the present invention provides a novel compound of formula Ia, wherein:
R1 is substituted with 0-2 substituents independently selected at each occurrence from the group R1a, CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, xe2x80x94(CH2)3xe2x80x94, CH3, xe2x80x94CO2OCH3, xe2x80x94CH2CH2OCH3, F, and CF3; and,
R1a is phenyl substituted with 0-2 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, Br, Cl, F, CF3, xe2x80x94CN, and SCH3.
[2o] In a still further preferred embodiment, the present invention provides a novel compound of formula Ia, wherein:
D is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, and CF3.
[2p] In another still further preferred embodiment, the present invention provides a novel compound of formula Ia, wherein:
D is pyridyl substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, and CF3.
[2q] In another more preferred embodiment, the present invention provides a novel compound of formula Ia, wherein:
R1 is selected from the group C1-10 alkyl, C2-10 alkenyl, C2-10alkynyl, C3-8 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl and C1-4 alkoxy-C1-4 alkyl;
R1 is substituted with a C3-8 cycloalkyl group, wherein 0-1 carbon atoms in the C4-8 cycloalkyl group is replaced by a group selected from the group xe2x80x94Oxe2x80x94, xe2x80x94S(O)nxe2x80x94, xe2x80x94NR13axe2x80x94, xe2x80x94NCO2R14bxe2x80x94, xe2x80x94NCORxe2x80x94 and xe2x80x94NSO2R14bxe2x80x94;
R1 is also substituted with 0-3 substituents independently selected at each occurrence from the group R1a, R1b, R1c, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94OR13a, xe2x80x94NR13aR16a, C1-2 alkoxy-C1-2 alkyl, and C3-8 cycloalkyl which is substituted with 0-1 R9 and in which 0-1 carbons of C4-8 cycloalkyl is replaced by xe2x80x94Oxe2x80x94;
provided that R1 is other than a cyclohexyl-(CH2)2xe2x80x94 group;
R1a is aryl and is selected from the group phenyl, naphthyl, indanyl and indenyl, each R1a being substituted with 0-1 xe2x80x94OR17 and 0-5 substituents independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94CN, nitro, SH, xe2x80x94S(O)nR18, xe2x80x94COR17, xe2x80x94OC(O)R18, xe2x80x94NR15aCOR17, xe2x80x94N(COR17)2, xe2x80x94NR15aCONR17aR19a, xe2x80x94NR15aCO2R18, xe2x80x94NR17aR19a, and xe2x80x94CONR17aR19a;
R1b is heteroaryl and is selected from the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-onyl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94CN, nitro, xe2x80x94OR17, SH, xe2x80x94S(O)mR18, xe2x80x94COR17, xe2x80x94OC(O)R18, xe2x80x94NR15aCOR17, xe2x80x94N(COR17)2, xe2x80x94NR15aCONR17aR19a, xe2x80x94NR15aCO2R18, xe2x80x94NR17aR19a, and xe2x80x94CONR17aR19a and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R15a, CO2R14b, COR14b and SO2R14b; and,
R1c is heterocyclyl and is a saturated or partially saturated heteroaryl, each heterocyclyl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94CN, nitro, xe2x80x94OR13a, SH, S(O)nR14b, xe2x80x94COR13a, xe2x80x94OC(O)R14b, xe2x80x94NR15aCOR13a, xe2x80x94N(COR13a)2, xe2x80x94NR15aCONR13aR16a, xe2x80x94NR15aCO2R14b, xe2x80x94NR13aR16a, and xe2x80x94CONR13aR16a and each heterocyclyl being substituted on any nitrogen atom with 0-1 substituents selected from the group R13a, CO2R14b, COR14b and SO2R14b and wherein any sulfur atom is optionally monooxidized or dioxidized.
[2r] In another even more preferred embodiment, the present invention provides a novel compound of formula Ia, wherein:
X is selected from the group O, S(O)n and a bond;
n is 0, 1 or 2;
R1 is selected from the group C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-8 cycloalkyl;
R1 is substituted with a C3-6 cycloalkyl group, wherein 0-1 carbon atoms in the C4-6 cycloalkyl group is replaced by a group selected from the group xe2x80x94Oxe2x80x94, xe2x80x94S(O)nxe2x80x94, and xe2x80x94NR13axe2x80x94;
R1 is also substituted with 0-2 substituents independently selected at each occurrence from the group R1a, R1b, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, Br, Cl, F, CF3, CF2CF3, xe2x80x94OR13a, xe2x80x94NR13aR16a, C1-2 alkoxy-C1-2 alkyl, and C3-6 cycloalkyl which is substituted with 0-1 R9 and in which 0-1 carbons of C4-8 cycloalkyl is replaced by xe2x80x94Oxe2x80x94;
R1a is aryl and is selected from the group phenyl and indanyl, each R1a being substituted with 0-1 xe2x80x94OR17 and 0-5 substituents independently selected at each occurrence from the group C1-4 alkyl, C3-6 cycloalkyl, Br, Cl, F, C1-4 haloalkyl, xe2x80x94CN, xe2x80x94S(O)nR18, xe2x80x94COR17, xe2x80x94NR17aR19a, and xe2x80x94CONR17aR19a;
R1b is heteroaryl and is selected from the group pyridyl, pyrimidinyl, furanyl, thienyl, imidazolyl, thiazolyl, pyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, and indazolyl, each heteroaryl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-4 alkyl, C3-6 cycloalkyl, Br, Cl, F, CF3, xe2x80x94CN, xe2x80x94OR17, xe2x80x94S(O)mR18, xe2x80x94COR17, xe2x80x94NR17aR19a, and xe2x80x94CONR17aR19a and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R15a, CO2R14b, COR14b and SO2R14b;
R2 is selected from the group C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl and is substituted with 0-1 substituents selected from the group xe2x80x94CN, OH, Cl, F, and C1-4 alkoxy;
R9 is independently selected at each occurrence from the group H, C1-4 alkyl and C3-8 cycloalkyl;
R3 and R8 are independently selected at each occurrence from the group H, Br, Cl, F, xe2x80x94CN, C1-4 alkyl, C3-6 cycloalkyl, C1-4 alkoxy, NH2, C1-4 alkylamino, and (C1-4 alkyl)2-amino;
R13 is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, C3-6 cycloalkyl-C1-2 alkyl, aryl(C1-2 alkyl)-, and heteroaryl(C1-2 alkyl)-;
R13a and R16a are independently selected at each occurrence from the group H, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-C1-6 alkyl;
R14 is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, C3-6 cycloalkyl-C1-2 alkyl, aryl(C1-2 alkyl)-, and heteroaryl(C1-2 alkyl)-;
R14a is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, and C3-6 cycloalkyl-C1-2 alkyl;
R14b is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-C1-2 alkyl;
R15 is independently selected at each occurrence from the group H, C1-4 alkyl, C3-7 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, phenyl and benzyl, each phenyl or benzyl being substituted on the aryl moiety with 0-3 groups chosen from the group C1-4 alkyl, Br, Cl, F, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and dimethylamino;
R15a is independently selected at each occurrence from the group H, C1-4 alkyl, C3-7 cycloalkyl, and C3-6 cycloalkyl-C1-6 alkyl;
R17, R18 and R19 are independently selected at each occurrence from the group H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, C1-2 alkoxy-C1-2 alkyl, and C1-4 haloalkyl;
alternatively, in an NR17R19 moiety, R17 and R19 taken together form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N4 in 1-piperazinyl is substituted with 0-1 substituents selected from the group R13, CO2R14, COR14 and SO2R14;
R17a and R19a are independently selected at each occurrence from the group H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl and C1-4 haloalkyl;
aryl is phenyl substituted with 1-4 substituents independently selected at each occurrence from the group C1-4 alkyl, C3-6 cycloalkyl, xe2x80x94OR17, Br, Cl, F, C1-4 haloalkyl, xe2x80x94CN, xe2x80x94S(O)nR18, xe2x80x94COR17, xe2x80x94CO2R17, xe2x80x94NR15COR17, xe2x80x94NR15CO2R18, xe2x80x94NR17R19, and xe2x80x94CONR17R19; and,
heteroaryl is independently selected at each occurrence from the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-on-yl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted 1-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, C1-4 haloalkyl, xe2x80x94CN, xe2x80x94OR17, xe2x80x94S(O)mR18, xe2x80x94COR17, xe2x80x94CO2R17, xe2x80x94OC(O)R18, xe2x80x94NR15COR17, xe2x80x94N(COR17)2, xe2x80x94NR15CO2R18, xe2x80x94NR17R19, and xe2x80x94CONR17R19 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R15, CO2R14a, COR14a and SO2R14a.
[2s] In another still more preferred embodiment, the present invention provides a novel compound of formula Ia, wherein:
X is selected from the group O, S and a bond;
R1 is C1-6 alkyl;
R is substituted with a C3-6 cycloalkyl, wherein 0-1 carbon atoms in the C4-6 cycloalkyl is replaced by a group selected from the group xe2x80x94Oxe2x80x94, xe2x80x94S(O)nxe2x80x94, and xe2x80x94NR13axe2x80x94;
R1 is also substituted with 0-2 substituents independently selected at each occurrence from the group R1a, R1b, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, F, CF3, xe2x80x94OR13a, xe2x80x94NR13aR16a, xe2x80x94CH2OCH3, xe2x80x94CH2CH2OCH3, and C3-6 cycloalkyl which is substituted with 0-1 CH3 and in which 0-1 carbons of C4-8 cycloalkyl is replaced by xe2x80x94Oxe2x80x94;
provided that R1 is other than a cyclohexyl-(CH2)2xe2x80x94 group;
R1a is aryl and is phenyl substituted with 0-1 substituents selected from OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, and OCF3, and 0-3 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, Br, Cl, F, CF3, xe2x80x94CN, SCH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2;
R1b is heteroaryl and is selected from the group furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, and indazolyl, each heteroaryl being substituted on 0-3 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH3, CO2CH3, COCH3 and SO2CH3;
R2 is selected from the group CH3, CH2CH3, CH(CH3)2, and CH2CH2CH3;
R3 and R8 are independently selected at each occurrence from the group H, CH3, CH2CH3, CH(CH3)2, and CH2CH2CH3;
aryl is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, SO2CH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2; and,
heteroaryl is independently selected at each occurrence from the group pyridyl, indolyl, benzothienyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, and benzoxazolin-2-on-yl, each heteroaryl being substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, SO2CH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH3, CO2CH3, COCH3 and SO2CH3.
[2t] In another further preferred embodiment, the present invention provides a novel compound of formula Ia, wherein:
R1 is (cyclopropyl)C1 alkyl or (cyclobutyl)C1 alkyl;
R1 is substituted with 1-2 substituents independently selected at each occurrence from the group R1a, R1b, CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, xe2x80x94(CH2)3CH3, xe2x80x94CHxe2x95x90CH2, xe2x80x94CHxe2x95x90CH(CH3), xe2x80x94CHxe2x89xa1CH, xe2x80x94CHxe2x89xa1C(CH3), xe2x80x94CH2OCH3, xe2x80x94CH2CH2OCH3, F, CF3, cyclopropyl, CH3-cyclopropyl, cyclobutyl, CH3-cyclobutyl, cyclopentyl, CH3-cyclopentyl;
R1a is phenyl substituted with 0-1 substituents selected from OCH3, OCH2CH3, and OCF3, and 0-2 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, Br, Cl, F, CF3, xe2x80x94CN, and SCH3;
R1b is heteroaryl and is selected from the group furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, and tetrazolyl, each heteroaryl being substituted on 0-3 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, OCH3, OCH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, and SCH3 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH3, CO2CH3, COCH3 and SO2CH3;
R2 is selected from the group CH3, CH2CH3, and CH(CH3)2;
R3 and R8 are independently selected at each occurrence from the group H and CH3;
aryl is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, SO2CH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2; and,
heteroaryl is pyridyl substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, SO2CH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2.
[2u] In another even further preferred embodiment, the present invention provides a novel compound of formula Ia, wherein:
R1 is (cyclopropyl)C1 alkyl or (cyclobutyl)C1 alkyl;
R1 is substituted with 1-2 substituents independently selected at each occurrence from the group R1a, R1b, CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, xe2x80x94(CH2)3CH3, xe2x80x94CHxe2x95x90CH2, xe2x80x94CHxe2x95x90CH(CH3), xe2x80x94CHxe2x89xa1CH, xe2x80x94CHxe2x89xa1C(CH3), xe2x80x94CH2OCH3, xe2x80x94CH2CH2OCH3, F, CF3, cyclopropyl, and CH3-cyclopropyl;
R1a is phenyl substituted with 0-2 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, Br, Cl, F, CF3, xe2x80x94CN, and SCH3;
R1b is heteroaryl and is selected from the group furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, and pyrazolyl, each heteroaryl being substituted on 0-3 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, OCH3, OCH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, and SCH3.
[2v] In another further preferred embodiment, the present invention provides a novel compound of formula Ia, wherein:
D is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, and CF3.
[2w] In another further preferred embodiment, the present invention provides a novel compound of formula Ia, wherein:
D is pyridyl substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, and CF3.
[3] In another preferred embodiment, the present invention provides a novel compound of formula Ib: 
[3a] In another more preferred embodiment, the present invention provides a novel compound of formula Ib, wherein:
X is selected from the group O, S(O)n and a bond;
n is 0, 1 or 2;
R1 is selected from the group C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-8 cycloalkyl;
R1 is substituted with 0-1 substituents selected from the group xe2x80x94CN, xe2x80x94S(O)nR14b, xe2x80x94COR13a, xe2x80x94CO2R13a, and C3-8 cycloalkyl, wherein 0-1 carbon atoms in the C4-8 cycloalkyl is replaced by a group selected from the group xe2x80x94Oxe2x80x94, xe2x80x94S(O)nxe2x80x94, xe2x80x94NR13axe2x80x94, xe2x80x94NCO2R14bxe2x80x94, xe2x80x94NCOR14bxe2x80x94 and xe2x80x94NSO2R14bxe2x80x94;
R1 is also substituted with 0-2 substituents independently selected at each occurrence from the group R1a, R1b, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, Br, Cl, F, CF3, CF2CF3, xe2x80x94OR13a, xe2x80x94NR13aR16a, C1-2 alkoxy-C1-2 alkyl, and C3-8 cycloalkyl which is substituted with 0-1 R9 and in which 0-1 carbons of C4-8 cycloalkyl is replaced by xe2x80x94Oxe2x80x94;
provided that R1 is other than a cyclohexyl-(CH2)2xe2x80x94 group;
R1a is aryl and is selected from the group phenyl and indanyl, each R1a being substituted with 0-1 xe2x80x94OR17 and 0-5 substituents independently selected at each occurrence from the group C1-4 alkyl, C3-6 cycloalkyl, Br, Cl, F, C1-4 haloalkyl, xe2x80x94CN, xe2x80x94S(O)nR18, xe2x80x94COR17, xe2x80x94NR17aR19a, and xe2x80x94CONR17aR19a;
R1b is heteroaryl and is selected from the group pyridyl, pyrimidinyl, furanyl, thienyl, imidazolyl, thiazolyl, pyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, and indazolyl, each heteroaryl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-4 alkyl, C3-6 cycloalkyl, Br, Cl, F, CF3, xe2x80x94CN, xe2x80x94OR17, xe2x80x94S(O)mR18, xe2x80x94COR17, xe2x80x94NR17aR19a, and xe2x80x94CONR17aR19a and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R15a, CO2R14b, COR14b and SO2R14b;
provided that R1 is other than a xe2x80x94(CH2)1-4-aryl or xe2x80x94(CH2)1-4-heteroaryl wherein the aryl or heteroaryl group is substituted or unsubstituted;
R2 is selected from the group C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl and is substituted with 0-1 substituents selected from the group xe2x80x94CN, OH, Cl, F, and C1-4 alkoxy;
R3 and R7 are independently selected at each occurrence from the group H, Br, Cl, F, xe2x80x94CN, C1-4 alkyl, C3-6 cycloalkyl, C1-4 alkoxy, NH2, C1-4 alkylamino, and (C1-4 alkyl)2-amino;
R9 is independently selected at each occurrence from the group H, C1-4 alkyl and C3-8 cycloalkyl;
R13 is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, C3-6 cycloalkyl-C1-2 alkyl, aryl(C1-2 alkyl)-, and heteroaryl(C1-2 alkyl)-;
R13a and R16a are independently selected at each occurrence from the group H, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-C1-6 alkyl;
R14 is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, C3-6 cycloalkyl-C1-2 alkyl, aryl(C1-2 alkyl)-, and heteroaryl(C1-2 alkyl)-;
R14a is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, and C3-6 cycloalkyl-C1-2 alkyl;
R14b is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-C1-2 alkyl;
R15 is independently selected at each occurrence from the group H, C1-4 alkyl, C3-7 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, phenyl and benzyl, each phenyl or benzyl being substituted on the aryl moiety with 0-3 groups chosen from the group C1-4 alkyl, Br, Cl, F, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and dimethylamino;
R15a is independently selected at each occurrence from the group H, C1-4 alkyl, C3-7 cycloalkyl, and C3-6 cycloalkyl-C1-6 alkyl;
R17, R18 and R19 are independently selected at each occurrence from the group H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, C1-2 alkoxy-C1-2 alkyl, and C1-4 haloalkyl;
alternatively, in an NR17R19 moiety, R17 and R19 taken together form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N4 in 1-piperazinyl is substituted with 0-1 substituents selected from the group R13, CO2R14, COR14 and SO2R14;
R17a and R19a are independently selected at each occurrence from the group H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl and C1-4 haloalkyl;
aryl is phenyl substituted with 1-4 substituents independently selected at each occurrence from the group C1-4 alkyl, C3-6 cycloalkyl, xe2x80x94OR17, Br, Cl, F, C1-4 haloalkyl, xe2x80x94CN, xe2x80x94S(O)nR18, xe2x80x94COR17, xe2x80x94CO2R17, xe2x80x94NR15COR17, xe2x80x94NR15CO2R18, xe2x80x94NR17R19, and xe2x80x94CONR17R19; and,
heteroaryl is independently selected at each occurrence from the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-on-yl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted 1-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, C1-4 haloalkyl, xe2x80x94CN, xe2x80x94OR17, xe2x80x94S(O)mR18, xe2x80x94COR17, xe2x80x94CO2R17, xe2x80x94OC(O)R18, xe2x80x94NR15COR17, xe2x80x94N(COR17)2, xe2x80x94NR15CO2R18, xe2x80x94NR17R19, and xe2x80x94CONR17R19 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R15, CO2R14a, COR14a and SO2R14a.
[3b] In another even more preferred embodiment, the present invention provides a novel compound of formula Ib, wherein:
X is selected from the group O, S and a bond;
R1 is substituted C1-6 alkyl;
R1 is substituted with 0-1 substituents selected from the group xe2x80x94CN, xe2x80x94CO2R13a, and C3-8 cycloalkyl, wherein 0-1 carbon atoms in the C4-8 cycloalkyl is replaced by a group selected from the group xe2x80x94Oxe2x80x94, xe2x80x94S(O)nxe2x80x94, and xe2x80x94NR13axe2x80x94;
R1 is also substituted with 0-2 substituents independently selected at each occurrence from the group R1a, R1b, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, Br, Cl, F, CF3, xe2x80x94OR13a, NR13aR16a, C1-2 alkoxy-C1-2 alkyl, and C3-6 cycloalkyl which is substituted with 0-1 CH3 and in which 0-1 carbons of C4-8 cycloalkyl is replaced by xe2x80x94Oxe2x80x94;
provided that R1 is other than a cyclohexyl-(CH2)2xe2x80x94 group;
R1a is aryl and is phenyl substituted with 0-1 substituents selected from OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, and OCF3, and 0-3 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, Br, Cl, F, CF3, xe2x80x94CN, SCH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2;
R1b is heteroaryl and is selected from the group furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, and indazolyl, each heteroaryl being substituted on 0-3 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH3, CO2CH3, COCH3 and SO2CH3;
provided that R1 is other than a xe2x80x94(CH2)1-4-aryl or xe2x80x94(CH2)1-4-heteroaryl wherein the aryl or heteroaryl group is substituted or unsubstituted;
R2 is selected from the group CH3, CH2CH3, CH(CH3)2, and CH2CH2CH3;
R3 and R7 are independently selected at each occurrence from the group H, CH3, CH2CH3, CH(CH3)2, and CH2CH2CH3;
aryl is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, SO2CH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2; and,
heteroaryl is independently selected at each occurrence from the group pyridyl, indolyl, benzothienyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, and benzoxazolin-2-on-yl, each heteroaryl being substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, SO2CH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH3, CO2CH3, COCH3 and SO2CH3.
[3c] In another still more preferred embodiment, the present invention provides a novel compound of formula Ib, wherein:
R1 is substituted C1;
R1 is substituted with 0-1 substituents selected from the group xe2x80x94CN, xe2x80x94CO2CH3, and xe2x80x94CO2CH2CH3;
R1 is also substituted with 0-2 substituents independently selected at each occurrence from the group R1a, R1b, CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, xe2x80x94(CH2)3CH3, xe2x80x94CHxe2x95x90CH2, xe2x80x94CHxe2x95x90CH(CH3), xe2x80x94CHxe2x89xa1CH, xe2x80x94CHxe2x89xa1C(CH3), xe2x80x94CH2OCH3, xe2x80x94CH2CH2OCH3, F, CF3, cyclopropyl, CH3-cyclopropyl, cyclobutyl, CH3-cyclobutyl, cyclopentyl, CH3-cyclopentyl;
R1a is phenyl substituted with 0-1 substituents selected from OCH3, OCH2CH3, and OCF3, and 0-2 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, Br, Cl, F, CF3, xe2x80x94CN, and SCH3;
R1b is heteroaryl and is selected from the group furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, and tetrazolyl, each heteroaryl being substituted on 0-3 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, OCH3, OCH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, and SCH3 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH3, CO2CH3, COCH3 and SO2CH3;
provided that R1 is other than a xe2x80x94(CH2)1-4-aryl or xe2x80x94(CH2)1-4-heteroaryl wherein the aryl or heteroaryl group is substituted or unsubstituted;
R2 is selected from the group CH3, CH2CH3, and CH(CH3)2;
R3 and R7 are independently selected at each occurrence from the group H and CH3;
aryl is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, SO2CH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2; and,
heteroaryl is pyridyl substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, SO2CH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2.
[3d] In another further preferred embodiment, the present invention provides a novel compound of formula Ib, wherein:
R1 is substituted (cyclopropyl)-C1 alkyl or (cyclobutyl)-C1 alkyl;
R1 is substituted with 0-1 xe2x80x94CN;
R1 is also substituted with 0-1 substituents independently selected at each occurrence from the group R1a, R1b, CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, xe2x80x94(CH2)3CH3, xe2x80x94CHxe2x95x90CH2, xe2x80x94CHxe2x95x90CH(CH3), xe2x80x94CHxe2x89xa1CH, xe2x80x94CHxe2x89xa1C(CH3), Br, Cl, F, CF3, cyclopropyl, and CH3-cyclopropyl;
R1 is also substituted with 0-1 substituents independently selected at each occurrence from the group R1a, R1b, CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, xe2x80x94(CH2)3CH3, xe2x80x94CHxe2x95x90CH2, xe2x80x94CHxe2x95x90CH(CH3), xe2x80x94CHxe2x89xa1CH, xe2x80x94CHxe2x89xa1C(CH3), xe2x80x94CH2OCH3, xe2x80x94CH2CH2OCH3, F, CF3, cyclopropyl, and CH3-cyclopropyl;
R1b is heteroaryl and is selected from the group furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, and pyrazolyl, each heteroaryl being substituted on 0-3 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, OCH3, OCH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, and SCH3.
[3e] In another further preferred embodiment, the present invention provides a novel compound of formula Ib, wherein:
R1 is (cyclopropyl)C1 alkyl or (cyclobutyl)-C1 alkyl substituted with 1 substituent independently selected at each occurrence from the group R1a, R1b, CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, xe2x80x94(CH2)3CH3, xe2x80x94CHxe2x95x90CH2, xe2x80x94CHxe2x95x90CH(CH3), xe2x80x94CHxe2x89xa1CH, xe2x80x94CHxe2x89xa1C(CH3), xe2x80x94CH2OCH3, xe2x80x94CH2CH2OCH3, F, CF3, cyclopropyl, and CH3-cyclopropyl;
R1a is phenyl substituted with 0-2 substituents independently selected at each occurrence from the group CH3, CH2CH3, Cl, F, and CF3;
R1b is heteroaryl and is selected from the group furanyl, thienyl, and isoxazolyl, each heteroaryl being substituted on 0-2 carbon atoms with a substituent independently selected at each occurrence from the group CH3, OCH3, Cl, F, and CF3.
[3f] In an even further preferred embodiment, the present invention provides a novel compound of formula Ib, wherein:
R1 is selected from the group (cyclopropyl)CHxe2x80x94CH3, (cyclopropyl)CHxe2x80x94CH2CH3, (cyclopropyl))CHxe2x80x94CH2OCH13, (cyclopropyl)CHxe2x80x94CH2CH2CH3, (cyclopropyl)CHxe2x80x94CH2CH2OCH3, (cyclopropyl)2CH, phenyl(cyclopropyl)CH, furanyl(cyclopropyl)CH, thienyl(cyclopropyl)CH, isoxazolyl(cyclopropyl)CH, (CH3-furanyl)(cyclopropyl)CH, (cyclobutyl)CHxe2x80x94CH3, (cyclobutyl)CHxe2x80x94CH2CH3, (cyclobutyl)CHxe2x80x94CH2OCH3, (cyclobutyl)CHxe2x80x94CH2CH2CH3, (cyclobutyl)CHxe2x80x94CH2CH2OCH3, (cyclobutyl)2CH, phenyl(cyclobutyl)CH, furanyl(cyclobutyl)CH, thienyl(cyclobutyl)CH, isoxazolyl(cyclobutyl)CH, and (CH3-furanyl)(cyclobutyl)CH;
[3g] In another further preferred embodiment, the present invention provides a novel compound of formula Ib, wherein:
D is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, and CF3.
[3h] in another further preferred embodiment, the present invention provides a novel compound of formula Ib, wherein:
D is pyridyl substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, and CF3.
[3i] In another preferred embodiment, the present invention provides a novel compound of formula Ib, wherein the compound is selected from the group:
1-(1-cyclopropylpropyl)-4-(2,4-dichlorophenyl)-2-ethyl-1H-imidazo [4,5-c]pyridine;
1-(1-cyclopropylpropyl)-4-(2,4-dichlorophenyl)-2-methoxy-1H-imidazo[4,5-c]pyridine;
1-(1-cyclopropylpropyl)-2-ethyl-4-[2-methyl-4-(trifluoromethyl)phenyl]-1H-imidazo[4,5-c]pyridine;
4-[2-chloro-4-(trifluoromethyl)phenyl]-1-(1-cyclopropylpropyl)-2-ethyl-1H-imidazo[4,5-c]pyridine;
4-[2-chloro-4-(trifluoromethyl)phenyl]-1-(1-cyclopropylpropyl)-2-methoxy-1H-imidazo[4,5-c]pyridine;
4-[2-chloro-4-(trifluoromethyl)phenyl]-1-(1-cyclopropylpropyl)-2-(methylsulfanyl)-1H-imidazo[4,5-c]pyridine;
4-(2-chloro-4-methoxyphenyl)-1-(1-cyclopropylpropyl)-2-ethyl-1H-imidazo[4,5-c]pyridine;
4-(2-chloro-4-methoxyphenyl)-1-(1-cyclopropylpropyl)-2-methoxy-1H-imidazo[4,5-c]pyridine;
1-(1-cyclopropylpropyl)-2-ethyl-4-(4-methoxy-2,5-dimethylphenyl)-1H-imidazo[4,5-c]pyridine;
1-(1-cyclopropylpropyl)-2-methoxy-4-(4-methoxy-2,5-dimethylphenyl)-1H-imidazo[4,5-c]pyridine;
4-(2-chloro-4-methoxyphenyl)-1-(1-cyclopropylpropyl)-2-ethyl-1H-imidazo[4,5-c]pyridine;
4-(2-chloro-4-methoxyphenyl)-1-(1-cyclopropylpropyl)-2-methoxy-1H-imidazo[4,5-c]pyridine;
4-(2-chloro-5-fluoro-4-methoxyphenyl)-1-(1-cyclopropylpropyl)-2-ethyl-1H-imidazo[4,5-c]pyridine;
4-(2-chloro-fluoro-4-methoxyphenyl)-1-(1-cyclopropylpropyl)-2-methoxy-1H-imidazo[4,5-c]pyridine;
4-(2-chloro-5-fluoro-4-methylphenyl)-1-(1-cyclopropylpropyl)-2-ethyl-1H-imidazo[4,5-c]pyridine;
2,4-(2-chloro-fluoro-4-methylphenyl)-1-(1-cyclopropylpropyl)-2-methoxy-1H-imidazo[4,5-c]pyridine;
1-(1-cyclopropylpropyl)-2-methoxy-4-(2,4,5-trimethylphenyl)-1H-imidazo[4,5-c]pyridine;
1-(1-cyclopropylpropyl)-2-ethyl-4-(2,4,5-trimethylphenyl)-1H-imidazo[4,5-c]pyridine;
1-(1-cyclopropylpropyl)-2-ethyl-4-(2,5,6-trimethyl-3-pyridinyl)-1H-imidazo[4,5-c]pyridine
1-(1-cyclopropylpropyl)-2-methoxy-4-(2,5,6-trimethyl-3-pyridinyl)-1H-imidazo[4,5-c]pyridine;
1-(1-cyclopropylpropyl)-4-(2,6-dimethyl-3-pyridinyl)-2-ethyl-1H-imidazo[4,5-c]pyridine;
1-(1-cyclopropylpropyl)-4-(2,6-dimethyl-3-pyridinyl)-2-methoxy-1H-imidazo[4,5-c]pyridine;
1-(1-cyclopropylpropyl)-4-(2,6-dimethoxy-3-pyridinyl)-2-ethyl-1H-imidazo[4,5-c]pyridine;
4-(2,4-dichlorophenyl)-2-ethyl-1-(1-ethylpropyl)-1H-imidazo[4,5-c]pyridine;
4-(2,4-dichlorophenyl)-1-(1-ethylpropyl)-2-methoxy-1H-imidazo[4,5-c]pyridine;
4-[2-chloro-4-(trifluoromethyl)phenyl]-1-(1-ethylpropyl)-2-methoxy-1H-imidazo[4,5-c]pyridine;
4-[2-chloro-4-(trifluoromethyl)phenyl]-2-ethyl-1-(1-ethylpropyl)-1H-imidazo[4,5-c]pyridine;
4-[2-chloro-4-(methylsulfonyl)phenyl]-2-ethyl-1-(1-ethylpropyl)-1H-imidazo[4,5-c]pyridine;
4-[2-chloro-4-(methylsulfonyl)phenyl]-1-(1-ethylpropyl)-2-methoxy-1H-imidazo[4,5-c]pyridine;
2-ethyl-1-(1-ethylpropyl)-4-(4-methoxy-2,5-dimethylphenyl)-1H-imidazo[4,5-c]pyridine;
1-(1-ethylpropyl)-2-methoxy-4-(4-methoxy-2,5-dimethylphenyl)-1H-imidazo[4,5-c]pyridine;
4-(2-chloro-4-methoxyphenyl)-2-ethyl-1-(1-ethylpropyl)-1H-imidazo[4,5-c]pyridine;
4-(2-chloro-4-methoxyphenyl)-1-(1-ethylpropyl)-2-methoxy-1H-imidazo[4,5-c]pyridine;
2-ethyl-1-(1-ethylpropyl)-4-[4-methoxy-2-(trifluoromethyl)phenyl]-1H-imidazo[4,5-c]pyridine;
1-(1-ethylpropyl)-2-methoxy-4-[4-methoxy-2-(trifluoromethyl)phenyl]-1H-imidazo[4,5-c]pyridine;
1-(1-ethylpropyl)-4-(5-fluoro-4-methoxy-2-methylphenyl)-2-methoxy-1H-imidazo[4,5-c]pyridine;
2-ethyl-1-(1-ethylpropyl)-4-(5-fluoro-4-methoxy-2-methylphenyl)-1H-imidazo[4,5-c]pyridine;
3-chloro-4-[1-(1-ethylpropyl)-2-methoxy-1H-imidazo[4,5-c]pyridin-4-yl]benzonitrile;
3-chloro-4-[2-ethyl-1-(1-ethylpropyl)-1H-imidazo[4,5-c]pyridin-4-yl]benzonitrile;
1-{3-chloro-4-[2-ethyl-1-(1-ethylpropyl)-1H-imidazo[4,5-c]pyridin-4-yl]phenyl}-1-ethanone;
1-{3-chloro-4-[1-(1-ethylpropyl)-2-methoxy-1H-imidazo[4,5-c]pyridin-4-yl]phenyl}-1-ethanone;
1-(dicyclopropylmethyl)-2-ethyl-4-(5-fluoro-4-methoxy-2-methylphenyl)-1H-imidazo[4,5-c]pyridine;
1-(dicyclopropylmethyl)-4-(5-fluoro-4-methoxy-2-methylphenyl)-2-methoxy-1H-imidazo[4,5-c]pyridine;
4-(2-chloro-4-methoxyphenyl)-1-(dicyclopropylmethyl)-2-ethyl-1H-imidazo[4,5-c]pyridine;
4-(2-chloro-4-methoxyphenyl)-1-(dicyclopropylmethyl)-2-methoxy-1H-imidazo[4,5-c]pyridine;
4-(2,4-dichlorophenyl)-1-(dicyclopropylmethyl)-2-ethyl-1H-imidazo[4,5-c]pyridine;
4-(2,4-dichlorophenyl)-1-(dicyclopropylmethyl)-2-methoxy-1H-imidazo[4,5-c]pyridine;
4-[2-chloro-4-(trifluoromethyl)phenyl]-1-(dicyclopropylmethyl)-2-ethyl-1H-imidazo[4,5-c]pyridine;
4-[2-chloro-4-(trifluoromethyl)phenyl]-1-(dicyclopropylmethyl)-2-methoxy-1H-imidazo[4,5-c]pyridine;
4-(2,4-dichlorophenyl)-1-(1-ethyl-3-methoxypropyl)-2-methoxy-1H-imidazo[4,5-c]pyridine;
4-(2,4-dichlorophenyl)-2-ethyl-1-(1-ethyl-3-methoxypropyl)-1H-imidazo[4,5-c]pyridine;
4-[2-chloro-4-(trifluoromethyl)phenyl]-1-(1-ethyl-3-methoxypropyl)-2-methoxy-1H-imidazo[4,5-c]pyridine;
4-[2-chloro-4-(trifluoromethyl)phenyl]-2-ethyl-1-(1-ethyl-3-methoxypropyl)-1H-imidazo[4,5-c]pyridine;
4-(2-chloro-4-methoxyphenyl)-1-(1-ethyl-3-methoxypropyl)-2-methoxy-1H-imidazo[4,5-c]pyridine;
4-(2-chloro-4-methoxyphenyl)-2-ethyl-1-(1-ethyl-3-methoxypropyl)-1H-imidazo[4,5-c]pyridine;
4-(2-chloro-5-fluoro-4-methoxyphenyl)-1-(1-ethyl-3-methoxypropyl)-2-methoxy-1H-imidazo[4,5-c]pyridine;
4-(2-chloro-5-fluoro-4-methoxyphenyl)-2-ethyl-1-(1-ethyl-3-methoxypropyl)-1H-imidazo[4,5-c]pyridine;
1-(1-ethyl-3-methoxypropyl)-2-methoxy-4-(4-methoxy-2,5-dimethylphenyl)-1H-imidazo[4,5-c]pyridine;
2-ethyl-1-(1-ethyl-3-methoxypropyl)-4-(4-methoxy-2,5-dimethylphenyl)-1H-imidazo[4,5-c]pyridine;
2-ethyl-1-(1-ethyl-3-methoxypropyl)-4-(5-fluoro-4-methoxy-2-methylphenyl)-1H-imidazo[4,5-c]pyridine;
1-(1-ethyl-3-methoxypropyl)-4-(5-fluoro-4-methoxy-2-methylphenyl)-2-methoxy-1H-imidazo[4,5-c]pyridine;
4-(2-chloro-5-fluoro-4-methylphenyl)-1-(1-ethyl-3-methoxypropyl)-2-methoxy-1H-imidazo[4,5-c]pyridine;
4-(2-chloro-5-fluoro-4-methylphenl)-2-ethyl-1-(1-ethyl-3-methoxypropyl)-1H-imidazo[4,5-c]pyridine;
4-[2-chloro-4-(methylsulfonyl)phenyl]-1-(1-ethyl-3-methoxypropyl)-2-methoxy-1H-imidazo[4,5-c]pyridine;
4-[2-chloro-4-(methylsulfonyl)phenyl]-2-ethyl-1-(1-ethyl-3-methoxypropyl)-1H-imidazo[4,5-c]pyridine;
1-{3-chloro-4-[1-(1-ethyl-3-methoxypropyl)-2-methoxy-1H-imidazo[4,5-c]pyridin-4-yl]phenyl}-1-ethanone;
1-{3-chloro-4-[2-ethyl-1-(1-ethyl-3-methoxypropyl)-1H-imidazo[4,5-c]pyridin-4-yl]phenyl}-1-ethanone;
1-{5-[1-(1-ethyl-3-methoxypropyl)-2-methoxy-1H-imidazo[4,5-c]pyridin-4-yl]-6-methyl-2-pyridinyl}-1-ethanone;
1-{5-[2-ethyl-1-(1-ethyl-3-methoxypropyl)-1H-imidazo[4,5-c]pyridin-4-yl]-6-methyl-2-pyridinyl}-1-ethanone;
1-(1-ethyl-3-methoxypropyl)-2-methoxy-4-(6-methoxy-2-methyl-3-pyridinyl)-1H-imidazo[4,5-c]pyridine;
2-ethyl-1-(1-ethyl-3-methoxypropyl)-4-(6-methoxy-2-methyl-3-pyridinyl)-1H-imidazo[4,5-c]pyridine;
4-(2,6-dimethoxy-3-pyridinyl)-2-ethyl-1-(1-ethyl-3-methoxypropyl)-1H-imidazo[4,5-c]pyridine;
4-(2,6-dimethoxy-3-pyridinyl)-1-(1-ethyl-3-methoxypropyl)-2-methoxy-1H-imidazo[4,5-c]pyridine;
4-(2,6-dimethyl-3-pyridinyl)-1-(1-ethyl-3-methoxypropyl)-2-methoxy-1H-imidazo[4,5-c]pyridine;
4-(2,6-dimethyl-3-pyridinyl)-2-ethyl-1-(1-ethyl-3-methoxypropyl)-1H-imidazo[4,5-c]pyridine;
2-ethyl-1-(1-ethyl-3-methoxypropyl)-4-(2,5,6-trimethyl-3-pyridinyl)-1H-imidazo[4,5-c]pyridine;
1-(1-ethyl-3-methoxypropyl)-2-methoxy-4-(2,5,6-trimethyl-3-pyridinyl)-1H-imidazo[4,5-c]pyridine;
4-(2,4-dichlorophenyl)-2-ethyl-1-[1-(methoxymethyl)propyl]-1H-imidazo[4,5-c]pyridine;
4-(2,4-dichlorophenyl)-2-methoxy-1-[1-(methoxymethyl)propyl]-1H-imidazo[4,5-c]pyridine;
4-[2-chloro-4-(trifluoromethyl)phenyl]-2-ethyl-1-[1-(methoxymethyl)propyl]-1H-imidazo[4,5-c]pyridine;
4-[2-chloro-4-(trifluoromethyl)phenyl]-2-methoxy-1-[1-(methoxymethyl)propyl]-1H-imidazo[4,5-c]pyridine;
4-(2-chloro-5-fluoro-4-methylphenyl)-2-ethyl-1-[1-(methoxymethyl)propyl]-1H-imidazo[4,5-c]pyridine;
4-(2-chloro-5-fluoro-4-methylphenyl)-2-methoxy-1-[1-(methoxymethyl)propyl]-1H-imidazo[4,5-c]pyridine;
2-methoxy-4-(4-methoxy-2,5-dimethylphenyl)-1-[1-(methoxymethyl)propyl]-1H-imidazo[4,5-c]pyridine;
2-ethyl-4-(4-methoxy-2,5-dimethylphenyl)-1-[1-(methoxymethyl)propyl]-1H-imidazo[4,5-c]pyridine;
2-ethyl-4-(5-fluoro-4-methoxy-2-methylphenyl)-1-[1-(methoxymethyl)propyl]-1H-imidazo[4,5-c]pyridine;
4-(5-fluoro-4-methoxy-2-methylphenyl)-2-methoxy-1-[1-(methoxymethyl)propyl]-1H-imidazo[4,5-c]pyridine;
2-methoxy-1-[1-(methoxymethyl)propyl]-4-(6-methoxy-2-methyl-3-pyridinyl)-1H-imidazo[4,5-c]pyridine;
2-ethyl-1-[1-(methoxymethyl)propyl]-4-(6-methoxy-2-methyl-3-pyridinyl)-1H-imidazo[4,5-c]pyridine;
4-(2,6-dimethoxy-3-pyridinyl)-2-ethyl-1-[1-(methoxymethyl)propyl]-1H-imidazo[4,5-c]pyridine;
4-(2,6-dimethoxy-3-pyridinyl)-2-methoxy-1-[1-(methoxymethyl)propyl]-1H-imidazo[4,5-c]pyridine;
4-(2,6-dimethyl-3-pyridinyl)-2-ethyl-1-[1-(methoxymethyl)propyl]-1H-imidazo[4,5-c]pyridine;
4-(2,6-dimethyl-3-pyridinyl)-2-methoxy-1-[1-(methoxymethyl)propyl]-1H-imidazo[4,5-c]pyridine;
2-ethyl-1-(1-(methoxymethyl)propyl]-4-(2,5,6-trimethyl-3-pyridinyl)-1H-imidazo[4,5-c]pyridine;
2-methoxy-1-[1-(methoxymethyl)propyl]-4-(2,5,6-trimethyl-3-pyridinyl)-1H-imidazo[4,5-c]pyridine;
4-[2-chloro-4-(methylsulfonyl)phenyl]-2-ethyl-1-[1-(methoxymethyl)propyl]-1H-imidazo[4,5-c]pyridine; and
4-[2-chloro-4-(methylsulfonyl)phenyl]-2-methoxy-1-[1-(methoxymethyl)propyl]-1H-imidazo[4,5-c]pyridine;
or a pharmaceutically acceptable salt form thereof.
[3j] In another more preferred embodiment, the present invention provides a novel compound of formula Ib, wherein:
R1 is C3-8 cycloalkyl;
R1 is substituted with 0-1 substituents selected from the group xe2x80x94CN, xe2x80x94S(O)nR14b, xe2x80x94COR13a, xe2x80x94CO2R13a, xe2x80x94NR15aCOR13a, xe2x80x94N(COR13a)2, xe2x80x94NR15aCONR13aR16a, xe2x80x94NR15aCO2R14b, xe2x80x94CONR13aR16a, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, and C4-8 cycloalkyl, wherein 0-1 carbon atoms in the C4-8 cycloalkyl is replaced by a group selected from the group xe2x80x94Oxe2x80x94, xe2x80x94S(O)nxe2x80x94, xe2x80x94NR13axe2x80x94, xe2x80x94NCO2R14bxe2x80x94, xe2x80x94NCOR14bxe2x80x94 and xe2x80x94NSO2R14bxe2x80x94, and wherein N4 in 1-piperazinyl is substituted with 0-1 substituents selected from the group R13a, CO2R14b, COR14b and SO2R14b; and,
R1 is also substituted with 0-3 substituents independently selected at each occurrence from the group R1a, R1b, R1c, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94OR13a, C1-2 alkoxy-C1-2 alkyl, and xe2x80x94NR13aR16a.
[3k] In another even more preferred embodiment, the present invention provides a novel compound of formula Ib, wherein:
X is selected from the group O, S(O)n and a bond;
n is 0, 1 or 2;
R1 is selected from the group cyclopropyl, cyclobutyl, and cyclopentyl;
R1 is substituted with 0-1 substituents selected from the group xe2x80x94CN, xe2x80x94S(O)nR14b, xe2x80x94COR13a, xe2x80x94CO2R13a, and C4-8 cycloalkyl, wherein one carbon atom in the C4-8 cycloalkyl is replaced by a group selected from the group xe2x80x94Oxe2x80x94, xe2x80x94S(O)nxe2x80x94, xe2x80x94NR13axe2x80x94, xe2x80x94NCO2R14bxe2x80x94, NCOR14bxe2x80x94 and xe2x80x94NSO2R14bxe2x80x94;
R1 is also substituted with 0-2 substituents independently selected at each occurrence from the group R1a, R1b, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, Br, Cl, F, CF3, CF2CF3, xe2x80x94OR13a, C1-2 alkoxy-C1-2 alkyl, and xe2x80x94NR13aR16a;
R1a is aryl and is selected from the group phenyl and indanyl, each R1a being substituted with 0-1 xe2x80x94OR17 and 0-5 substituents independently selected at each occurrence from the group C1-4 alkyl, C3-6 cycloalkyl, Br, Cl, F, C1-4 haloalkyl, xe2x80x94CN, xe2x80x94S(O)nR18, xe2x80x94COR17, xe2x80x94NR17aR19a, and xe2x80x94CONR17aR19a;
R1b is heteroaryl and is selected from the group pyridyl, pyrimidinyl, furanyl, thienyl, imidazolyl, thiazolyl, pyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, and indazolyl, each heteroaryl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-4 alkyl, C3-6 cycloalkyl, Br, Cl, F, CF3, xe2x80x94CN, xe2x80x94OR17, xe2x80x94S(O)mR18, xe2x80x94COR17, xe2x80x94NR17aR19a, and xe2x80x94CONR17aR19a and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R15a, CO2R14b, COR14b and SO2R14b;
R2 is selected from the group C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl and is substituted with 0-1 substituents selected from the group xe2x80x94CN, OH, Cl, F, and C1-4 alkoxy;
R9 is independently selected at each occurrence from the group H, C1-4 alkyl and C3-8 cycloalkyl;
R3 and R7 are independently selected at each occurrence from the group H, Br, Cl, F, xe2x80x94CN, C1-4 alkyl, C3-6 cycloalkyl, C1-4 alkoxy, NH2, C1-4 alkylamino, and (C1-4 alkyl)2-amino;
R13 is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, C3-6 cycloalkyl-C1-2 alkyl, aryl(C1-2 alkyl)-, and heteroaryl(C1-2 alkyl)-;
R13a and R16a are independently selected at each occurrence from the group H, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-C1-6 alkyl;
R14 is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, C3-6 cycloalkyl-C1-2 alkyl, aryl(C1-2 alkyl)-, and heteroaryl(C1-2 alkyl)-;
R14a is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, and C3-6 cycloalkyl-C1-2 alkyl;
R14b is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-C1-2 alkyl;
R15 is independently selected at each occurrence from the group H, C1-4 alkyl, C3-7 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, phenyl and benzyl, each phenyl or benzyl being substituted on the aryl moiety with 0-3 groups chosen from the group C1-4 alkyl, Br, Cl, F, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and dimethylamino;
R15a is independently selected at each occurrence from the group H, C1-4 alkyl, C3-7 cycloalkyl, and C3-6 cycloalkyl-C1-6 alkyl;
R17, R18 and R19 are independently selected at each occurrence from the group H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, C1-2 alkoxy-C1-2 alkyl, and C1-4 haloalkyl;
alternatively, in an NR17R19 moiety, R17 and R19 taken together form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N4 in 1-piperazinyl is substituted with 0-1 substituents selected from the group R13, CO2R14, COR14 and SO2R14;
R17a and R19a are independently selected at each occurrence from the group H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl and C1-4 haloalkyl;
aryl is phenyl substituted with 1-4 substituents independently selected at each occurrence from the group C1-4 alkyl, C3-6 cycloalkyl, xe2x80x94OR17, Br, Cl, F, C1-4 haloalkyl, xe2x80x94CN, xe2x80x94S(O)nR18, xe2x80x94COR17, xe2x80x94CO2R17, xe2x80x94NR15COR17, xe2x80x94NR15CO2R18, xe2x80x94NR17R19, and xe2x80x94CONR17R19; and,
heteroaryl is independently selected at each occurrence from the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-on-yl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted 1-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, C1-4 haloalkyl, xe2x80x94CN, xe2x80x94OR17, xe2x80x94S(O)mR18, xe2x80x94COR17, xe2x80x94CO2R17, xe2x80x94OC(O)R18, xe2x80x94NR15COR17, xe2x80x94N(COR17)2, xe2x80x94NR15CO2R18, xe2x80x94NR17R19, and xe2x80x94CONR17R19 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R15, CO2R14a, COR14a and SO2R14a.
[3l] In another still more preferred embodiment, the present invention provides a novel compound of formula Ib, wherein:
X is selected from the group O, S and a bond;
R1 is substituted with 0-1 substituents selected from the group xe2x80x94CN, xe2x80x94CO2R13a, and C4-8 cycloalkyl, wherein 0-1 carbon atoms in the C4-8 cycloalkyl is replaced by a group selected from the group xe2x80x94Oxe2x80x94, xe2x80x94S(O)nxe2x80x94, and xe2x80x94NR13axe2x80x94;
R1 is also substituted with 0-2 substituents independently selected at each occurrence from the group R1a, R1b, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, Br, Cl, F, CF3, CF3, xe2x80x94OR13a, xe2x80x94OH, xe2x80x94OCH3, xe2x80x94OCH2CH3, xe2x80x94CH2OCH3, xe2x80x94CH2CH2OCH3, and xe2x80x94NR13aR16a;
R1a is aryl and is phenyl substituted with 0-1 substituents selected from OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, and OCF3, and 0-3 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, Br, Cl, F, CF3, xe2x80x94CN, SCH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2;
R1b is heteroaryl and is selected from the group furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, and indazolyl, each heteroaryl being substituted on 0-3 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH3, CO2CH3, COCH3 and SO2CH3;
R2 is selected from the group CH3, CH2CH3, CH(CH3)2, and CH2CH2CH3;
R3 and R7 are independently selected at each occurrence from the group H, CH3, CH2CH3, CH(CH3)2, and CH2CH2CH3;
aryl is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, SO2CH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2; and,
heteroaryl is independently selected at each occurrence from the group pyridyl, indolyl, benzothienyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, and benzoxazolin-2-on-yl, each heteroaryl being substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, SO2CH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH3, CO2CH3, COCH3 and SO2CH3.
[3m] In another further preferred embodiment, the present invention provides a novel compound of formula Ib, wherein:
R1 is substituted with 0-2 substituents independently selected at each occurrence from the group R1a, R1b, CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, xe2x80x94(CH2)3CH3, xe2x80x94CHxe2x95x90CH2, xe2x80x94CHxe2x95x90CH(CH3), xe2x80x94CHxe2x89xa1CH, xe2x80x94CHxe2x89xa1C(CH3), xe2x80x94CH2OCH3, xe2x80x94CH2CH2OCH3, F, and CF3;
R1a is phenyl substituted with 0-1 substituents selected from OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, and OCF3, and 0-2 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, Br, Cl, F, CF3, xe2x80x94CN, and SCH3;
R1b is heteroaryl and is selected from the group furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, and tetrazolyl, each heteroaryl being substituted on 0-3 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, OCH3, OCH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, and SCH3 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH3, CO2CH3, COCH3 and SO2CH3;
R2 is selected from the group CH3, CH2CH3, and CH(CH3)2;
R3 and R7 are independently selected at each occurrence from the group H and CH3;
aryl is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, SO2CH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2; and,
heteroaryl is pyridyl substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, SO2CH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2.
[3n] In another even further preferred embodiment, the present invention provides a novel compound of formula Ib, wherein:
R1 is substituted with 0-2 substituents independently selected at each occurrence from the group R1a, CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, xe2x80x94(CH2)3CH3, xe2x80x94CH2OCH3, xe2x80x94CH2CH2OCH3, F, and CF3; and,
R1a is phenyl substituted with 0-2 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, Br, Cl, F, CF3, xe2x80x94CN, and SCH3.
[3o] In another still further preferred embodiment, the present invention provides a novel compound of formula Ib, wherein:
D is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, and CF3.
[3p] In another still further preferred embodiment, the present invention provides a novel compound of formula Ib, wherein:
D is pyridyl substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, and CF3.
[3q] In another more preferred embodiment, the present invention provides a novel compound of formula Ib, wherein:
R1 is selected from the group C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-8 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl and C1-4 alkoxy-C1-4 alkyl;
R1 is substituted with a C3-8 cycloalkyl group, wherein 0-1 carbon atoms in the C4-8 cycloalkyl group is replaced by a group selected from the group xe2x80x94Oxe2x80x94, xe2x80x94S(O)nxe2x80x94, xe2x80x94NR13axe2x80x94, xe2x80x94NCO2R14bxe2x80x94, xe2x80x94NCOR14bxe2x80x94 and xe2x80x94NSO2R14bxe2x80x94;
R1 is also substituted with 0-3 substituents independently selected at each occurrence from the group R1a, R1b, R1c, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94OR13a, xe2x80x94NR13aR16a, C1-2alkoxy-C1-2 alkyl, and C3-8 cycloalkyl which is substituted with 0-1 R9 and in which 0-1 carbons of C4-8 cycloalkyl is replaced by xe2x80x94Oxe2x80x94;
provided that R1 is other than a cyclohexyl-(CH2)2xe2x80x94 group;
R1a is aryl and is selected from the group phenyl, naphthyl, indanyl and indenyl, each R1a being substituted with 0-1 xe2x80x94OR17 and 0-5 substituents independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94CN, nitro, SH, xe2x80x94S(O)nR18, xe2x80x94COR17, xe2x80x94OC(O)R18, xe2x80x94NR15aCOR17, xe2x80x94N(COR17)2, xe2x80x94NR15aCONR17aR19a, xe2x80x94NR15aCO2R18, xe2x80x94NR17aR19a, and xe2x80x94CONR17aR19a;
R1b is heteroaryl and is selected from the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-onyl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94CN, nitro, xe2x80x94OR17, SH, xe2x80x94S(O)mR18, xe2x80x94COR17, xe2x80x94OC(O)R18, xe2x80x94NR15aCOR17h, xe2x80x94N(COR17)2, xe2x80x94NR15aCONR17aR19a, xe2x80x94NR15aCO2R18, xe2x80x94NR17aR19a, and xe2x80x94CONR17aR19a and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R15a, CO2R14b, COR14b and SO2R14b; and,
R1c is heterocyclyl and is a saturated or partially saturated heteroaryl, each heterocyclyl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94CN, nitro, xe2x80x94OR13a, SH, xe2x80x94S(O)nR14b, xe2x80x94COR13a, xe2x80x94OC(O)R14b, xe2x80x94NR15aCOR13a, xe2x80x94N(COR13a)2, xe2x80x94NR15aCONR13aR16a, xe2x80x94NR15aCO2R14b, xe2x80x94NR13aR16a, and xe2x80x94CONR13aR16a and each heterocyclyl being substituted on any nitrogen atom with 0-1 substituents selected from the group R13a, CO2R14b, COR14b and SO2R14b and wherein any sulfur atom is optionally monooxidized or dioxidized.
[3r] In another even more preferred embodiment, the present invention provides a novel compound of formula Ib, wherein:
X is selected from the group O, S(O)n and a bond;
n is 0, 1 or 2;
R1 is selected from the group C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl;
R1 is substituted with a C3-6 cycloalkyl group, wherein 0-1 carbon atoms in the C4-6 cycloalkyl group is replaced by a group selected from the group xe2x80x94Oxe2x80x94, xe2x80x94S(O)nxe2x80x94, and xe2x80x94NR13axe2x80x94;
R1 is also substituted with 0-2 substituents independently selected at each occurrence from the group R1a, R1b, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, Br, Cl, F, CF3, CF2CF3, xe2x80x94OR13a, xe2x80x94NR13aR16a, C1-2 alkoxy-C1-2 alkyl, and C3-6 cycloalkyl which is substituted with 0-1 R9 and in which 0-1 carbons of C4-8 cycloalkyl is replaced by xe2x80x94Oxe2x80x94;
R1a is aryl and is selected from the group phenyl and indanyl, each R1a being substituted with 0-1 xe2x80x94OR17 and 0-5 substituents independently selected at each occurrence from the group C1-4 alkyl, C3-6 cycloalkyl, Br, Cl, F, C1-4 haloalkyl, xe2x80x94CN, xe2x80x94S(O)nR18, xe2x80x94COR17, xe2x80x94NR17aR19a, and xe2x80x94CONR17aR19a;
R1b is heteroaryl and is selected from the group pyridyl, pyrimidinyl, furanyl, thienyl, imidazolyl, thiazolyl, pyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, and indazolyl, each heteroaryl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-4 alkyl, C3-6 cycloalkyl, Br, Cl, F, CF3, xe2x80x94CN, xe2x80x94OR17, xe2x80x94S(O)mR18, xe2x80x94COR17, xe2x80x94NR17aR19a, and xe2x80x94CONR17aR19a and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R15a, CO2R14b, COR14b and SO2R14b;
R2 is selected from the group C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl and is substituted with 0-1 substituents selected from the group xe2x80x94CN, OH, Cl, F, and C1-4 alkoxy;
R9 is independently selected at each occurrence from the group H, C1-4 alkyl and C3-8 cycloalkyl;
R3 and R7 are independently selected at each occurrence from the group H, Br, Cl, F, xe2x80x94CN, C1-4 alkyl, C3-6 cycloalkyl, C1-4 alkoxy, NH2, C1-4 alkylamino, and (C1-4 alkyl)2-amino;
R13 is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, C3-6 cycloalkyl-C1-2 alkyl, aryl(C1-2 alkyl)-, and heteroaryl(C1-2 alkyl)-;
R13a and R16a are independently selected at each occurrence from the group H, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-C1-6 alkyl;
R14 is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, C3-6 cycloalkyl-C1-2 alkyl, aryl(C1-2 alkyl)-, and heteroaryl(C1-2 alkyl)-;
R14a is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, and C3-6 cycloalkyl-C1-2 alkyl;
R14b is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-C1-2 alkyl;
R15 is independently selected at each occurrence from the group H, C1-4 alkyl, C3-7 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, phenyl and benzyl, each phenyl or benzyl being substituted on the aryl moiety with 0-3 groups chosen from the group C1-4 alkyl, Br, Cl, F, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and dimethylamino;
R15a is independently selected at each occurrence from the group H, C1-4 alkyl, C3-7 cycloalkyl, and C3-6 cycloalkyl-C1-6 alkyl;
R17, R18 and R19 are independently selected at each occurrence from the group H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, C1-2 alkoxy-C1-2 alkyl, and C1-4 haloalkyl;
alternatively, in an NR17R19 moiety, R17 and R19 taken together form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N4 in 1-piperazinyl is substituted with 0-1 substituents selected from the group R13, CO2R14, COR14 and SO2R14;
R17a and R19a are independently selected at each occurrence from the group H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl and C1-4 haloalkyl;
aryl is phenyl substituted with 1-4 substituents independently selected at each occurrence from the group C1-4 alkyl, C3-6 cycloalkyl, xe2x80x94OR17, Br, Cl, F, C1-4 haloalkyl, xe2x80x94CN, xe2x80x94S(O)nR18, xe2x80x94COR17, xe2x80x94CO2R17, xe2x80x94NR15COR17, xe2x80x94NR15CO2R18, xe2x80x94NR17R19, and xe2x80x94CONR17R19; and,
heteroaryl is independently selected at each occurrence from the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-on-yl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted 1-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, C1-4 haloalkyl, xe2x80x94CN, xe2x80x94OR17, xe2x80x94S(O)mR18, xe2x80x94COR17, xe2x80x94CO2R17, xe2x80x94OC(O)R18, xe2x80x94NR15COR17, xe2x80x94N(COR17)2, xe2x80x94NR15CO2R18, xe2x80x94NR17R19, and xe2x80x94CONR17R19 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R15, CO2R14a, COR14a and SO2R14a.
[3s] In another still more preferred embodiment, the present invention provides a novel compound of formula Ib, wherein:
X is selected from the group O, S and a bond;
R1 is C1-6 alkyl;
R1 is substituted with a C3-6 cycloalkyl, wherein 0-1 carbon atoms in the C4-4 cycloalkyl is replaced by a group selected from the group xe2x80x94Oxe2x80x94, xe2x80x94S(O)nxe2x80x94, and xe2x80x94NR13axe2x80x94;
R1 is also substituted with 0-2 substituents independently selected at each occurrence from the group R1a, R1b, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, F, CF3, xe2x80x94OR13a, xe2x80x94NR13aR16a, xe2x80x94CH2OCH3, xe2x80x94CH2CH2OCH3, and C3-6 cycloalkyl which is substituted with 0-1 CH3 and in which 0-1 carbons of C4-8 cycloalkyl is replaced by xe2x80x94Oxe2x80x94;
provided that R1 is other than a cyclohexyl-(CH2)2xe2x80x94 group;
R1a is aryl and is phenyl substituted with 0-1 substituents selected from OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, and OCF3, and 0-3 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, Br, Cl, F, CF3, xe2x80x94CN, SCH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2;
R1b is heteroaryl and is selected from the group furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, and indazolyl, each heteroaryl being substituted on 0-3 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH3, CO2CH3, COCH3 and SO2CH3;
R2 is selected from the group CH3, CH2CH3, CH(CH3)2, and CH2CH2CH3;
R3 and R7 are independently selected at each occurrence from the group H, CH3, CH2CH3, CH(CH3)2, and CH2CH2CH3;
aryl is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, SO2CH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2; and,
heteroaryl is independently selected at each occurrence from the group pyridyl, indolyl, benzothienyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, and benzoxazolin-2-on-yl, each heteroaryl being substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, SO2CH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH3, CO2CH3, COCH3 and SO2CH3.
[3t] In another further preferred embodiment, the present invention provides a novel compound of formula Ib, wherein:
R1 is (cyclopropyl)C1 alkyl or (cyclobutyl)C1 alkyl;
R1 is substituted with 1-2 substituents independently selected at each occurrence from the group R1a, R1b, CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, xe2x80x94(CH2)3CH3, xe2x80x94CHxe2x95x90CH2, xe2x80x94CHxe2x95x90CH(CH3), xe2x80x94CHxe2x89xa1CH, xe2x80x94CHxe2x89xa1C(CH3), xe2x80x94CH2OCH3, xe2x80x94CH2CH2OCH3, F, CF3, cyclopropyl, CH3-cyclopropyl, cyclobutyl, CH3-cyclobutyl, cyclopentyl, CH3-cyclopentyl;
R1a is phenyl substituted with 0-1 substituents selected from OCH3, OCH2CH3, and OCF3, and 0-2 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, Br, Cl, F, CF3, xe2x80x94CN, and SCH3;
R1b is heteroaryl and is selected from the group furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, and tetrazolyl, each heteroaryl being substituted on 0-3 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, OCH3, OCH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, and SCH3 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH3, CO2CH3, COCH3 and SO2CH3;
R2 is selected from the group CH3, CH2CH3, and CH(CH3)2;
R3 and R7 are independently selected at each occurrence from the group H and CH3;
aryl is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, SO2CH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2; and,
heteroaryl is pyridyl substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, SO2CH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2.
[3u] In another even further preferred embodiment, the present invention provides a novel compound of formula Ib, wherein:
R1 is (cyclopropyl)C1 alkyl or (cyclobutyl)C1 alkyl;
R1 is substituted with 1-2 substituents independently selected at each occurrence from the group R1a, R1b, CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, xe2x80x94(CH2)3CH3, xe2x80x94CHxe2x95x90CH2, xe2x80x94CHxe2x95x90CH(CH3), xe2x80x94CHxe2x89xa1CH, xe2x80x94CHxe2x89xa1C(CH3), xe2x80x94CH2OCH3, xe2x80x94CH2CH2OCH3, F, CF3, cyclopropyl, and CH3-cyclopropyl;
R1a is phenyl substituted with 0-2 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, Br, Cl, F, CF3, xe2x80x94CN, and SCH3;
R1b is heteroaryl and is selected from the group furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, and pyrazolyl, each heteroaryl being substituted on 0-3 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, OCH3, OCH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, and SCH3.
[3v] In another further preferred embodiment, the present invention provides a novel compound of formula Ib, wherein:
D is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, and CF3.
[3w] In another further preferred embodiment, the present invention provides a novel compound of formula Ib, wherein:
D is pyridyl substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, and CF3.
[4] In another preferred embodiment, the present invention provides a novel compound of formula Ic: 
[4a] In another more preferred embodiment, the present invention provides a novel compound of formula Ic, wherein:
X is selected from the group O, S(O)n and a bond;
n is 0, 1 or 2;
R1 is selected from the group C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-8 cycloalkyl;
R1 is substituted with 0-1 substituents selected from the group xe2x80x94CN, xe2x80x94S(O)nR14b, xe2x80x94COR13a, xe2x80x94CO2R13a, and C3-8 cycloalkyl, wherein 0-1 carbon atoms in the C4-8 cycloalkyl is replaced by a group selected from the group xe2x80x94Oxe2x80x94, xe2x80x94S(O)nxe2x80x94, xe2x80x94NR13axe2x80x94, xe2x80x94NCO2R14bxe2x80x94, xe2x80x94NCOR14bxe2x80x94 and xe2x80x94NSO2R14bxe2x80x94;
R1 is also substituted with 0-2 substituents independently selected at each occurrence from the group R1a, R1b, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, Br, Cl, F, CF3, CF2CF3, xe2x80x94OR13a, xe2x80x94NR13aR16a, C1-2 alkoxy-C1-2 alkyl, and C3-8 cycloalkyl which is substituted with 0-1 R9 and in which 0-1 carbons of C4-8 cycloalkyl is replaced by xe2x80x94Oxe2x80x94;
provided that R1 is other than a cyclohexyl-(CH2)2-group;
R1a is aryl and is selected from the group phenyl and indanyl, each R1a being substituted with 0-1 xe2x80x94OR17 and 0-5 substituents independently selected at each occurrence from the group C1-4 alkyl, C3-6 cycloalkyl, Br, Cl, F, C1-4 haloalkyl, xe2x80x94CN, xe2x80x94S(O)nR18, xe2x80x94COR17, xe2x80x94NR17aR19a, and xe2x80x94CONR17aR19a;
R1b is heteroaryl and is selected from the group pyridyl, pyrimidinyl, furanyl, thienyl, imidazolyl, thiazolyl, pyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, and indazolyl, each heteroaryl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-4 alkyl, C3-6 cycloalkyl, Br, Cl, F, CF3, xe2x80x94CN, xe2x80x94OR17, xe2x80x94S(O)mR18, xe2x80x94COR17, xe2x80x94NR17aR19a, and xe2x80x94CONR17aR19a and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R15a, CO2R14b, COR14b and SO2R14b;
provided that R1 is other than a xe2x80x94(CH2)1-4-aryl or xe2x80x94(CH2)1-4-heteroaryl wherein the aryl or heteroaryl group is substituted or unsubstituted;
R2 is selected from the group C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl and is substituted with 0-1 substituents selected from the group xe2x80x94CN, OH, Cl, F, and C1-4 alkoxy;
R3 is selected from the group H, Br, Cl, F, xe2x80x94CN, C1-4 alkyl, C3-6 cycloalkyl, C1-4 alkoxy, NH2, C1-4 alkylamino, and (C1-4 alkyl)2-amino;
R9 is independently selected at each occurrence from the group H, C1-4 alkyl and C3-8 cycloalkyl;
R13 is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, C3-6 cycloalkyl-C1-2 alkyl, aryl(C1-2 alkyl)-, and heteroaryl(C1-2 alkyl)-;
R13a and R16a are independently selected at each occurrence from the group H, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-C1-6 alkyl;
R14 is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, C3-6 cycloalkyl-C1-2 alkyl, aryl(C1-2 alkyl)-, and heteroaryl(C1-2 alkyl)-;
R14a is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, and C3-6 cycloalkyl-C1-2 alkyl;
R14b is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-C1-2 alkyl;
R15 is independently selected at each occurrence from the group H, C1-4 alkyl, C3-7 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, phenyl and benzyl, each phenyl or benzyl being substituted on the aryl moiety with 0-3 groups chosen from the group C1-4 alkyl, Br, Cl, F, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and dimethylamino;
R15a is independently selected at each occurrence from the group H, C1-4 alkyl, C3-7 cycloalkyl, and C3-6 cycloalkyl-C1-6 alkyl;
R17, R18 and R19 are independently selected at each occurrence from the group H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, C1-2 alkoxy-C1-2 alkyl, and C1-4 haloalkyl;
alternatively, in an NR17R19 moiety, R17 and R19 taken together form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N4 in 1-piperazinyl is substituted with 0-1 substituents selected from the group R13, CO2R14, COR14 and SO2R14;
R17a and R19a are independently selected at each occurrence from the group H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl and C1-4 haloalkyl;
aryl is phenyl substituted with 1-4 substituents independently selected at each occurrence from the group C1-4 alkyl, C3-6 cycloalkyl, xe2x80x94OR17, Br, Cl, F, C1-4 haloalkyl, xe2x80x94CN, xe2x80x94S(O)nR18, xe2x80x94COR17, xe2x80x94CO2R17, xe2x80x94NR15COR17, xe2x80x94NR15CO2R18, xe2x80x94NR17R19, and xe2x80x94CONR17R19; and,
heteroaryl is independently selected at each occurrence from the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-on-yl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted 1-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, C1-4 haloalkyl, xe2x80x94CN, xe2x80x94OR17, xe2x80x94S(O)mR18, xe2x80x94COR17, xe2x80x94CO2R17, xe2x80x94OC(O)R18, xe2x80x94NR15COR17, xe2x80x94N(COR17)2, xe2x80x94NR15CO2R18, xe2x80x94NR17R19, and xe2x80x94CONR17R19 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R15, CO2R14a, COR14a and SO2R14a.
[4b] In another even more preferred embodiment, the present invention provides a novel compound of formula Ic, wherein:
X is selected from the group O, S and a bond;
R1 is substituted C1-6 alkyl;
R1 is substituted with 0-1 substituents selected from the group xe2x80x94CN, xe2x80x94CO2R13a, and C3-8 cycloalkyl, wherein 0-1 carbon atoms in the C4-8 cycloalkyl is replaced by a group selected from the group xe2x80x94Oxe2x80x94, xe2x80x94S(O)nxe2x80x94, and xe2x80x94NR13a;
R1 is also substituted with 0-2 substituents independently selected at each occurrence from the group R1a, R1b, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, Br, Cl, F, CF3, xe2x80x94OR13a, xe2x80x94NR13aR16a, C1-2 alkoxy-C1-2 alkyl, and C3-6 cycloalkyl which is substituted with 0-1 CH3 and in which 0-1 carbons of C4-8 cycloalkyl is replaced by xe2x80x94Oxe2x80x94;
provided that R1 is other than a cyclohexyl-(CH2)2-group;
R1a is aryl and is phenyl substituted with 0-1 substituents selected from OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, and OCF3, and 0-3 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, Br, Cl, F, CF3, xe2x80x94CN, SCH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2;
R1b is heteroaryl and is selected from the group furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, and indazolyl, each heteroaryl being substituted on 0-3 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2xe2x80x94 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH3, CO2CH3, COCH3 and SO2CH3;
provided that R1 is other than a xe2x80x94(CH2)1-4-aryl or xe2x80x94(CH2)1-4-heteroaryl wherein the aryl or heteroaryl group is substituted or unsubstituted;
R2 is selected from the group CH3, CH2CH3, CH(CH3)2, and CH2CH2CH3;
R3 is selected from the group H, CH3, CH2CH3, CH(CH3)2, and CH2CH2CH3;
aryl is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, SO2CH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2; and,
heteroaryl is independently selected at each occurrence from the group pyridyl, indolyl, benzothienyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, and benzoxazolin-2-on-yl, each heteroaryl being substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, SO2CH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94CO(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH3, CO2CH3, COCH3 and SO2CH3.
[4c] In another still more preferred embodiment, the present invention provides a novel compound of formula Ic, wherein:
R1 is substituted C1;
R1 is substituted with 0-1 substituents selected from the group xe2x80x94CN, xe2x80x94CO2CH3, and xe2x80x94CO2CH2CH3;
R1 is also substituted with 0-2 substituents independently selected at each occurrence from the group R1a, R1b, CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, xe2x80x94(CH2)3CH3, xe2x80x94CHxe2x95x90CH2, xe2x80x94CHxe2x95x90CH(CH3), xe2x80x94CHxe2x89xa1CH, xe2x80x94CHxe2x89xa1C(CH3), xe2x80x94CH2OCH3, xe2x80x94CH2CH2OCH3, F, CF3, cyclopropyl, CH3-cyclopropyl, cyclobutyl, CH3-cyclobutyl, cyclopentyl, CH3-cyclopentyl;
R1a is phenyl substituted with 0-1 substituents selected from OCH3, OCH2CH3, and OCF3, and 0-2 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, Br, Cl, F, CF3, xe2x80x94CN, and SCH3;
R1b is heteroaryl and is selected from the group furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, and tetrazolyl, each heteroaryl being substituted on 0-3 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, OCH3, OCH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, and SCH3 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH3, CO2CH3, COCH3 and SO2CH3;
provided that R1 is other than a xe2x80x94(CH2)1-4-aryl or xe2x80x94(CH2)1-4-heteroaryl wherein the aryl or heteroaryl group is substituted or unsubstituted;
R2 is selected from the group CH3, CH2CH3, and CH(CH3)2;
R3 is selected from the group H and CH3;
aryl is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, SO2CH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2; and,
heteroaryl is pyridyl substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, SO2CH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2.
[4d] In another further preferred embodiment, the present invention provides a novel compound of formula Ic, wherein:
R1 is substituted (cyclopropyl)-C1 alkyl or (cyclobutyl)C1 alkyl;
R1 is substituted with 0-1 xe2x80x94CN;
R1 is also substituted with 0-1 substituents independently selected at each occurrence from the group R1a, R1b, CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, xe2x80x94(CH2)3CH3, xe2x80x94CHxe2x95x90CH2, xe2x80x94CHxe2x95x90CH(CH3), xe2x80x94CHxe2x89xa1CH, xe2x80x94CHxe2x89xa1C(CH3), xe2x80x94CH2OCH3, xe2x80x94CH2CH2OCHCH3, F, CF3, cyclopropyl, and CH3-cyclopropyl;
R1a is phenyl substituted with 0-1 substituents selected from OCH3, OCH2CH3, and OCF3, and 0-2 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, Br, Cl, F, CF3, xe2x80x94CN, and SCH3;
R1b is heteroaryl and is selected from the group furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, and pyrazolyl, each heteroaryl being substituted on 0-3 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, OCH3, OCH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, and SCH3.
[4e] In another further preferred embodiment, the present invention provides a novel compound of formula Ic, wherein:
R1 is (cyclopropyl)C1 alkyl or (cyclobutyl)-C1 alkyl substituted with 1 substituent independently selected at each occurrence from the group R1a, R1b, CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, xe2x80x94(CH2)3CH3, xe2x80x94CHxe2x95x90CH2, xe2x80x94CHxe2x95x90CH(CH3), xe2x80x94CHxe2x89xa1CH, xe2x80x94CHxe2x89xa1C(CH3), xe2x80x94CH2OCH3, xe2x80x94CH2CH2OCH3, F, CF3, cyclopropyl, and CH3-cyclopropyl;
R1a is phenyl substituted with 0-2 substituents independently selected at each occurrence from the group CH3, CH2CH3, Cl, F, and CF3;
R1b is heteroaryl and is selected from the group furanyl, thienyl, and isoxazolyl, each heteroaryl being substituted on 0-2 carbon atoms with a substituent independently selected at each occurrence from the group CH3, OCH3, C1, F, and CF3.
[4f] In an even further preferred embodiment, the present invention provides a novel compound of formula Ic, wherein:
R1 is selected from the group (cyclopropyl)CHxe2x80x94CH3, (cyclopropyl)CHxe2x80x94CH2CH3, (cyclopropyl)CHxe2x80x94CH2OCH3, (cyclopropyl)CHxe2x80x94CH2CH2CH3, (cyclopropyl)CHxe2x80x94CH2CH2OCH3, (cyclopropyl)2CH, phenyl(cyclopropyl)CH, furanyl(cyclopropyl)CH, thienyl(cyclopropyl)CH, isoxazolyl(cyclopropyl)CH, (CH3-furanyl)(cyclopropyl)CH, (cyclobutyl)CH-CH3, (cyclobutyl)CHxe2x80x94CH2CH3, (cyclobutyl)OHxe2x80x94OH2OCH3, (cyclobutyl)CHxe2x80x94CH2CH2CH3, (cyclobutyl)CHxe2x80x94CH2CH2OCH3, (cyclobutyl)2CH, phenyl(cyclobutyl)CH, furanyl(cyclobutyl)CH, thienyl(cyclobutyl)CH, isoxazolyl(cyclobutyl)CH, and (CH3-furanyl)(cyclobutyl)CH;
[4g] In another further preferred embodiment, the present invention provides a novel compound of formula Ic, wherein:
D is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, and CF3.
[4h] In another further preferred embodiment, the present invention provides a novel compound of formula Ic, wherein:
D is pyridyl substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, and CF3.
[4i] In another preferred embodiment, the present invention provides a novel compound of formula Ic, wherein the compound is selected from the group:
6-(2,4-bis(trifluoromethyl)phenyl-9-(dicyclopropylmethyl)-8-ethyl-9H-purine;
6-(2-chloro-4-cyanophenyl)-9-(dicyclopropylmethyl)-8-ethyl-9H-purine;
6-(2-chloro-4-methoxy-5-chlorophenyl)-9-(dicyclopropylmethyl)-8-ethyl-9H-purine;
6-(2-chloro-4-methoxy-5-methylphenyl)-9-(dicyclopropylmethyl)-8-ethyl-9H-purine;
6-(2-chloro-4-methoxyphenyl)-8-ethyl-9-(2-hexyl)-9H-purine;
6-(2-chloro-4-methoxyphenyl)-8-ethyl-9-(2-pentyl)-9H-purine;
6-(2-chloro-4-methoxyphenyl)-8-ethyl-9-(3-heptyl)-9H-purine;
6-(2-chloro-4-methoxyphenyl)-8-ethyl-9-(3-hexyl)-9H-purine;
6-(2-chloro-4-methoxyphenyl)-8-ethyl-9-(4-heptyl)-9H-purine;
6-(2-chloro-4-methoxyphenyl)-9-(1-cyclopropylbutyl)-8-ethyl-9H-purine;
6-(2-chloro-4-methoxyphenyl)-9-(1-cyclopropylpropyl)-8-ethyl-9H-purine;
6-(2-chloro-4-methoxyphenyl)-9-(dicyclopropylmethyl)-8-ethyl-9H-purine;
6-(2-chloro-4-methoxyphenyl)-9-(dicyclopropylmethyl)-8-methoxy-9H-purine;
6-(2-chloro-4-methyl-5-fluorophenyl)-9-(dicyclopropylmethyl)-8-ethyl-9H-purine;
6-(2-chloro-4-methylphenyl)-8-ethyl-9-(2-pentyl)-9H-purine;
6-(2-chloro-4-methylphenyl)-8-ethyl-9-(4-heptyl)-9H-purine;
6-(2-chloro-4-methylphenyl)-9-(1-cyclopropylbutyl)-8-ethyl-9H-purine;
6-(2-chloro-4-methylphenyl)-9-(dicyclopropylmethyl)-8-ethyl-9H-purine;
6-(2-chloro-4-trifluoromethoxyphenyl)-8-ethyl-9-(2-pentyl)-9H-purine;
6-(2-chloro-4-trifluoromethoxyphenyl)-8-ethyl-9-(3-hexyl)-9H-purine;
6-(2-chloro-4-trifluoromethoxyphenyl)-9-(1-cyclopropylbutyl)-8-ethyl-9H-purine;
6-(2-chloro-4-trifluoromethoxyphenyl)-9-(1-cyclopropylpropyl)-8-ethyl-9H-purine;
6-(2-chloro-4-trifluoromethoxyphenyl)-9-(dicyclopropylmethyl)-8-ethyl-9H-purine;
6-(2-chloro-4-trifluoromethylphenyl)-8-ethyl-9-(1-hexyn-3-yl)-9H-purine;
6-(2-chloro-4-trifluoromethylphenyl)-8-ethyl-9-(1-pentyn-3-yl)-9H-purine;
6-(2-chloro-4-trifluoromethylphenyl)-8-ethyl-9-(1-pentyn-4-yl)-9H-purine;
6-(2-chloro-4-trifluoromethylphenyl)-8-ethyl-9-(1-phenyl-2-butynyl)-9H-purine;
6-(2-chloro-4-trifluoromethylphenyl)-8-ethyl-9-(2-heptyn-4-yl)-9H-purine;
6-(2-chloro-4-trifluoromethylphenyl)8-ethyl-9-(2-hexyn-4-yl)-9H-purine;
6-(2-chloro-4-trifluoromethylphenyl)-8-ethyl-9-(2-pentyl)-9H-purine;
6-(2-chloro-4-trifluoromethylphenyl)-8-ethyl-9-(4-heptyl)-9H-purine;
6-(2-chloro-4-trifluoromethylphenyl)-8-ethyl-9-[(2-furanyl)-cyclopropylmethyl]-9H-purine;
6-(2-chloro-4-trifluoromethylphenyl)-8-ethyl-9-[1-(2-furanyl)propyl]-9H-purine;
6-(2-chloro-4-trifluoromethylphenyl)-9-(1-cyclobutylethyl)-8-ethyl-9H-purine;
6-(2-chloro-4-trifluoromethylphenyl)-9-(1-cyclopropyl-2-butynyl)-8-ethyl-9H-purine;
6-(2-chloro-4-trifluoromethylphenyl)-9-(1-cyclopropyl-2-propenyl)-8-ethyl-9H-purine;
6-(2-chloro-4-trifluoromethylphenyl)-9-(1-cyclopropylbutyl)-8-ethyl-9H-purine;
6-(2-chloro-4-trifluoromethylphenyl)-9-(1-cyclopropylpropyl)-8-ethyl-9H-purine;
6-(2-chloro-4-trifluoromethylphenyl)-9-(dicyclopropylmethyl)-8-ethyl-9H-purine;
6-(2-chloro-4-trifluoromethylphenyl)-9-(dicyclopropylmethyl)-8-methoxy-9H-purine;
6-(2-chloro-4-trifluoromethylphenyl)-9-[1-cyclopropyl-1-(2-thienyl)methyl]-8-ethyl-9H-purine;
9-(1-cyclobutylethyl)-6-(2,4-dichlorophenyl)-8-ethyl-9H-purine;
9-[1-cyclopropyl-(3-methylisoxazol-5-yl)methyl]-6-(2,4-dichlorophenyl)-8-ethyl-9H-purine;
9-(1-cyclopropyl-2-butynyl)-6-(2,4-dichlorophenyl)-8-ethyl-9H-purine;
9-(1-cyclopropyl-2-butynyl)-6-(2,4-dichlorophenyl)-8-ethyl-9H-purine;
9-(1-cyclopropyl-2-propenyl)-6-(2,4-dichloro-6-methylphenyl)-8-ethyl-9H-purine;
9-(1-cyclopropyl-2-propenyl)-6-(2,4-dichlorophenyl)-8-ethyl-9H-purine;
9-(1-cyclopropyl-2-propynyl)-8-ethyl-6-(2-trifluoromethyl-4-methoxyphenyl)-9H-purine;
9(1-cyclopropyl-4xe2x80x2-fluorobenzyl)-6-(2,4-dichlorophenyl)-8-ethyl-9H-purine;
9-(1-cyclopropylbenzyl)-6-(2,4-dichlorophenyl)-8-ethyl-9H-purine;
9-(1-cyclopropylbenzyl)-8-ethyl-6-(2-trifluoromethyl-4-methoxyphenyl)-9H-purine;
9-(1-cyclopropylbutyl)-6-(2,4-dichlorophenyl)-8-ethyl-9H-purine;
9-(1-cyclopropylbutyl)-8-ethyl-6-(2,4,6-trimethylphenyl)-9H-purine;
9-(1-cyclopropylbutyl)-8-ethyl-6-(2-methyl-4,5-dimethoxyphenyl)-9H-purine;
9-(1-cyclopropylbutyl)-8-ethyl-6-(2-methyl-4-chlorophenyl)-9H-purine;
9-(1-cyclopropylbutyl)-8-ethyl-6-(2-methyl-4-methoxyphenyl)-9H-purine;
9-(1-cyclopropylbutyl)-8-ethyl-6-(2-trifluoromethyl-4-chlorophenyl)-9H-purine;
9-(1-cyclopropylbutyl)-8-ethyl-6-(2-trifluoromethyl-4-methoxyphenyl)-9H-purine;
9-(1-cyclopropylethyl)-6-(2,4-dichlorophenyl)-8-ethyl-9H-purine;
9-(1-cyclopropylethyl)-8-ethyl-6-(2-trifluoromethyl-4-chlorophenyl)-9H-purine;
9-(1-cyclopropylpentyl)-8-ethyl-6-(2-methyl-4-methoxyphenyl)-9H-purine;
9-(1-cyclopropylpropyl)-6-(2,4-dichloro-6-methylphenyl)-8-ethyl-9H-purine;
9-(1-cyclopropylpropyl)-6-(2,4-dichlorophenyl)-8-ethyl-9H-purine;
9-(1-cyclopropylpropyl)-8-ethyl-6-(2,4,6-trimethylphenyl)-9H-purine;
9-(1-cyclopropylpropyl)-8-ethyl-6-(2-trifluoromethyl-4-chlorophenyl)-9H-purine;
6-(2,4-dichloro-5-fluorophenyl)-9-(dicyclopropylmethyl)-8-ethyl-9H-purine;
6-(2,4-dichloro-6-methylphenyl)-8-ethyl-9-(2-penten-3-yl)-9H-purine;
6-(2,4-dichloro-6-methylphenyl)-9-(dicyclopropylmethyl)-8-ethyl-9H-purine;
6-(2,4-dichlorophenyl)-8-ethyl-9-(1-hexyn-3-yl)-9H-purine;
6-(2,4-dichlorophenyl)-8-ethyl-9-(1-methoxycarbonylpropyl)-9H-purine;
6-(2,4-dichlorophenyl)-8-ethyl-9-(1-phenyl-2-butynyl)-9H-purine;
6-(2,4-dichlorophenyl)-8-ethyl-9-(2-heptyn-4-yl)-9H-purine;
6-(2,4-dichlorophenyl)-8-ethyl-9-(2-hexyl)-9H-purine;
6-(2,4-dichlorophenyl)-8-ethyl-9-(2-hexyn-4-yl)-9H-purine;
6-(2,4-dichlorophenyl)-8-ethyl-9-(2-penten-3-yl)-9H-purine;
6-(2,4-dichlorophenyl)-8-ethyl-9-(2-pentyl)-9H-purine;
6-(2,4-dichlorophenyl)-8-ethyl-9-(3-heptyl)-9H-purine;
6-(2,4-dichlorophenyl)-8-ethyl-9-(3-hexyl)-9H-purine;
6-(2,4-dichlorophenyl)-8-ethyl-9-(3-pentyl)-9H-purine;
6-(2,4-dichlorophenyl)-8-ethyl-9-(4-heptyl)-9H-purine;
6-(2,4-dichlorophenyl)-8-ethyl-9-[1-(2-methylcyclopropyl)ethyl]-9H-purine;
6-(2,4-dichlorophenyl)-9-(dicyclopropylmethyl)-8-ethyl-9H-purine;
6-(2,4-dichlorophenyl)-9-(dicyclopropylmethyl)-8-ethyl-9H-purine;
6-(2,4-dichlorophenyl)-9-(dicyclopropylmethyl)-8-methoxy-9H-purine;
6-(2,4-dichlorophenyl)-9-(diphenylmethyl)-8-ethyl-9H-purine;
9-(dicyclopropylmethyl)-6-(2,4-dimethylphenyl)-8-ethyl-9H-purine;
9-(dicyclopropylmethyl)-6-(2,4-dimethylphenyl)-8-ethyl-9H-purine;
9-(dicyclopropylmethyl)-6-(2,6-dimethoxypyridin-3-yl)-8-methoxy-9H-purine;
9-(dicyclopropylmethyl)-8-ethyl-6-(2,4,5-trichlorophenyl)-9H-purine;
9-(dicyclopropylmethyl)-8-ethyl-6-(2-methoxy-4-trifluoromethylphenyl)-9H-purine;
9-(dicyclopropylmethyl)-8-ethyl-6-(2-methyl-4,5-dimethoxyphenyl)-9H-purine;
9-(dicyclopropylmethyl)-8-ethyl-6-(2-methyl-4-chlorophenyl)-9H-purine;
9-(dicyclopropylmethyl)-8-ethyl-6-(2-methyl-4-dimethylaminophenyl)-9H-purine;
9-(dicyclopropylmethyl)-8-ethyl-6-(2-methyl-4-methoxy-5-chlorophenyl)-9H-purine;
9-(dicyclopropylmethyl)-8-ethyl-6-(2-methyl-4-methoxy-5-fluorophenyl)-9H-purine;
9-(dicyclopropylmethyl)-8-ethyl-6-(2-chloro-4-methoxy-5-fluorophenyl)-9H-purine;
9-(dicyclopropylmethyl)-8-ethyl-6-(2-methyl-4-methoxyphenyl)-9H-purine;
9-(dicyclopropylmethyl)-8-ethyl-6-(2-trifluoromethyl-4-chlorophenyl)-9H-purine;
9-(dicyclopropylmethyl)-8-ethyl-6-(2-trifluoromethyl-4-methoxyphenyl)-9H-purine;
9-(dicyclopropylmethyl)-8-ethyl-6-(2-trifluoromethyl-4-propyloxyphenyl)-9H-purine;
6-(2,6-dimethoxypyridin-3-yl)-8-ethyl-9-(2-pentyl)-9H-purine;
6-(2,4-dimethylphenyl)-8-ethyl-9-(2-pentyl)-9H-purine;
8-ethyl-6-(2-methyl-4,5-dimethoxyphenyl)-9-(2-pentyl)-9H-purine;
8-ethyl-6-(2-methyl-4,5-dimethoxyphenyl)-9-(3-pentyl)-9H-purine;
8-ethyl-9-(1-hexen-3-yl)-6-(2-methyl-4,5-dimethoxyphenyl)-9H-purine;
8-ethyl-9-(1-hexen-3-yl)-6-(2-trifluoromethyl-4-3methoxyphenyl)-9H-purine;
8-ethyl-9-(2-hexyl)-6-(2-trifluoromethyl-4-methoxyphenyl)-9H-purine;
8-ethyl-9-(2-pentyl)-6-(2-trifluoromethyl-4-methoxyphenyl)-9H-purine;
8-ethyl-9-(3-hexyl)-6-(2-methyl-4-methoxyphenyl)-9H-purine;
8-ethyl-9-(3-hexyl)-6-(2-trifluoromethyl-4-methoxyphenyl)-9H-purine;
8-ethyl-9-(3-pentyl)-6-(2-trifluoromethyl-4-chlorophenyl)-9H-purine;
8-ethyl-9-(4-heptyl)-6-(2-methyl-4-chlorophenyl)-9H-purine;
8-ethyl-9-(4-heptyl)-6-(2-methyl-4-methoxyphenyl)-9H-purine;
8-ethyl-9-(4-heptyl)-6-(2-trifluoromethyl-4-chlorophenyl)-9H-purine;
8-ethyl-9-(4-heptyl)-6-(2-trifluoromethyl-4 methoxyphenyl)-9H-purine; and
9-(dicyclopropylmethyl)-8-ethyl-6-(2-methyl-6-methoxy-3-pyridyl)-9H-purine;
or a pharmaceutically acceptable salt form thereof.
[4j] In another more preferred embodiment, the present invention provides a novel compound of formula Ic, wherein:
R1 is C3-8 cycloalkyl;
R1 is substituted with 0-1 substituents selected from the group xe2x80x94CN, xe2x80x94S(O)nR14b, COR13a, xe2x80x94CO2R13a, xe2x80x94NR15aCOR13a, xe2x80x94N(COR13a)2, xe2x80x94NR15aCONR13aR16a, xe2x80x94NR15aCO2R14b, xe2x80x94CONR13aR16a, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, and C4-8 cycloalkyl, wherein 0-1 carbon atoms in the C4-8 cycloalkyl is replaced by a group selected from the group xe2x80x94Oxe2x80x94, xe2x80x94S(O)nxe2x80x94, NR13axe2x80x94, xe2x80x94NCO2R14bxe2x80x94, xe2x80x94NCOR14bxe2x80x94 and xe2x80x94NSO2R14bxe2x80x94, and wherein N4 in 1-piperazinyl is substituted with 0-1 substituents selected from the group R13a, CO2R14b, COR14b and SO2R14b; and,
R1 is also substituted with 0-3 substituents independently selected at each occurrence from the group R1a, R1b, R1c, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94OR13a, C1-2 alkoxy-C1-2 alkyl, and xe2x80x94NR13aR16a.
[4k] In another even more preferred embodiment, the present invention provides a novel compound of formula Ic, wherein:
X is selected from the group O, S(O)n and a bond;
n is 0, 1 or 2;
R1 is selected from the group cyclopropyl, cyclobutyl, and cyclopentyl;
R1 is substituted with 0-1 substituents selected from the group xe2x80x94CN, xe2x80x94S(O)nR14b, xe2x80x94COR13a, xe2x80x94CO2R13a, and C4-8 cycloalkyl, wherein one carbon atom in the C4-8 cycloalkyl is replaced by a group selected from the group xe2x80x94Oxe2x80x94, xe2x80x94S(O)nxe2x80x94, xe2x80x94NR13axe2x80x94, xe2x80x94NCO2R14bxe2x80x94, xe2x80x94NCOR14bxe2x80x94 and xe2x80x94NSO2R14bxe2x80x94;
R1 is also substituted with 0-2 substituents independently selected at each occurrence from the group R1a, R1b, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, Br, Cl, F, CF3, CF2CF3, xe2x80x94OR13a, C1-2 alkoxy-C1-2 alkyl, and xe2x80x94NR13aR16a;
R1a is aryl and is selected from the group phenyl and indanyl, each R1a being substituted with 0-1 xe2x80x94OR17 and 0-5 substituents independently selected at each occurrence from the group C1-4 alkyl, C3-6 cycloalkyl, Br, Cl, F, C1-4 haloalkyl, xe2x80x94CN, xe2x80x94S(O)nR18, xe2x80x94COR17, xe2x80x94NR17aR19a, and xe2x80x94CONR17aR19a;
R1b is heteroaryl and is selected from the group pyridyl, pyrimidinyl, furanyl, thienyl, imidazolyl, thiazolyl, pyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, and indazolyl, each heteroaryl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-4 alkyl, C3-6 cycloalkyl, Br, Cl, F, CF3, xe2x80x94CN, xe2x80x94OR17, xe2x80x94S(O)mR18, xe2x80x94COR17, xe2x80x94NR17aR19a, and xe2x80x94CONR17aR19a and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R15a, CO2R14b, COR14b and SO2R14b;
R2 is selected from the group C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl and is substituted with 0-1 substituents selected from the group xe2x80x94CN, OH, Cl , F, and C1-4 alkoxy;
R9 is independently selected at each occurrence from the group H, C1-4 alkyl and C3-8 cycloalkyl;
R3 is selected from the group H, Br, Cl, F, xe2x80x94CN, C1-4 alkyl, C3-6 cycloalkyl, C1-4 alkoxy, NH2, C1-4 alkylamino, and (C1-4 alkyl)2-amino;
R13 is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, C3-6 cycloalkyl-C1-2 alkyl, aryl(C1-2 alkyl)-, and heteroaryl(C1-2 alkyl)-;
R13a and R16a are independently selected at each occurrence from the group H, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-C1-6 alkyl;
R14 is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, C3-6 cycloalkyl-C1-2 alkyl, aryl(C1-2 alkyl)-, and heteroaryl(C1-2 alkyl)-;
R14a is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, and C3-6 cycloalkyl-C1-2 alkyl;
R14b is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-C1-2 alkyl;
R15 is independently selected at each occurrence from the group H, C1-4 alkyl, C3-7 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, phenyl and benzyl, each phenyl or benzyl being substituted on the aryl moiety with 0-3 groups chosen from the group C1-4 alkyl, Br, Cl, F, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and dimethylamino;
R15a is independently selected at each occurrence from the group H, C1-4 alkyl, C3-7 cycloalkyl, and C3-6 cycloalkyl-C1-6 alkyl;
R17, R18 and R19 are independently selected at each occurrence from the group H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, C1-2 alkoxy-C1-2 alkyl, and C1-4 haloalkyl;
alternatively, in an NR17R19 moiety, R17 and R19 taken together form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N4 in 1-piperazinyl is substituted with 0-1 substituents selected from the group R13, CO2R14, COR14 and SO2R14;
R17a and R19a are independently selected at each occurrence from the group H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl and C1-4 haloalkyl;
aryl is phenyl substituted with 1-4 substituents independently selected at each occurrence from the group C1-4 alkyl, C3-6 cycloalkyl, xe2x80x94OR17, Br, Cl, F, C1-4 haloalkyl, xe2x80x94CN, xe2x80x94S(O)nR18, xe2x80x94COR17, xe2x80x94CO2R17, xe2x80x94NR15COR17, xe2x80x94NR15CO2R18, xe2x80x94NR17R19, and xe2x80x94CONR17R19; and,
heteroaryl is independently selected at each occurrence from the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-on-yl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted 1-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, C1-4 haloalkyl, xe2x80x94CN, xe2x80x94OR17, xe2x80x94S(O)mR18, xe2x80x94COR17, xe2x80x94CO2R17, xe2x80x94OC(O)R18, xe2x80x94NR15COR17, xe2x80x94N(COR17)2, xe2x80x94NR15CO2R18, xe2x80x94NR17R19, and xe2x80x94CONR17R19 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R15, CO2R14a, COR14a and SO2R14a.
[4l] In another still more preferred embodiment, the present invention provides a novel compound of formula Ic, wherein:
X is selected from the group O, S and a bond;
R1 is substituted with 0-1 substituents selected from the group xe2x80x94CN, xe2x80x94CO2R13a, and C4-8 cycloalkyl, wherein 0-1 carbon atoms in the C4-8 cycloalkyl is replaced by a group selected from the group xe2x80x94Oxe2x80x94, xe2x80x94S(O)nxe2x80x94, and xe2x80x94NR 13axe2x80x94;
R1 is also substituted with 0-2 substituents independently selected at each occurrence from the group R1a, R1b, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, Br, Cl, F, CF3, CF3, xe2x80x94OR13a, xe2x80x94OH, xe2x80x94OCH3, xe2x80x94OCH2CH3, xe2x80x94CH2OCH3, xe2x80x94CH2CH2OCH3, and NR13aR16a;
R1a is aryl and is phenyl substituted with 0-1 substituents selected from OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, and OCF3, and 0-3 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, Br, Cl, F, CF3, xe2x80x94CN, SCH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2;
R1b is heteroaryl and is selected from the group furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, and indazolyl, each heteroaryl being substituted on 0-3 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH3, CO2CH3, COCH3 and SO2CH3;
R2 is selected from the group CH3, CH2CH3, CH(CH3)2, and CH2CH2CH3;
R3 is selected from the group H, CH3, CH2CH3, CH(CH3)2, and CH2CH2CH3;
aryl is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, SO2CH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2; and,
heteroaryl is independently selected at each occurrence from the group pyridyl, indolyl, benzothienyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, and benzoxazolin-2-on-yl, each heteroaryl being substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, SO2CH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH3, CO2CH3, COCH3 and SO2CH3.
[4m] In another further preferred embodiment, the present invention provides a novel compound of formula Ic, wherein:
R1 is substituted with 0-2 substituents independently selected at each occurrence from the group R1a, R1b, CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, xe2x80x94(CH2)3CH3, xe2x80x94CHxe2x95x90CH2, xe2x80x94CHxe2x95x90CH(CH3), xe2x80x94CHxe2x89xa1CH, xe2x80x94CHxe2x89xa1C(CH3), xe2x80x94CH2OCH3, xe2x80x94CH2OH2OCH3, F, and CF3;
R1a is phenyl substituted with 0-1 substituents selected from OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, and OCF3, and 0-2 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, Br, Cl, F, CF3, xe2x80x94CN, and SCH3;
R1b is heteroaryl and is selected from the group furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, and tetrazolyl, each heteroaryl being substituted on 0-3 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, OCH3, OCH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, and SCH3 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH3, CO2CH3, COCH3 and SO2CH3;
R2 is selected from the group CH3, CH2CH3, and CH(CH3)2;
R3 is selected from the group H and CH3;
aryl is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, SO2CH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2; and,
heteroaryl is pyridyl substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, SO2CH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2.
[4n] In another even further preferred embodiment, the present invention provides a novel compound of formula Ic, wherein:
R1 is substituted with 0-2 substituents independently selected at each occurrence from the group R1a, CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, xe2x80x94(CH2)3CH3, xe2x80x94CH2OCH3, xe2x80x94CH2CH2OCH3, F, and CF3; and,
R1a is phenyl substituted with 0-2 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, Br, Cl, F, CF3, xe2x80x94CN, and SCH3.
[4o] In another still further preferred embodiment, the present invention provides a novel compound of formula Ic, wherein:
D is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, and CF3.
[4p] In another still further preferred embodiment, the present invention provides a novel compound of formula Ic, wherein:
D is pyridyl substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, and CF3.
[4q] In another more preferred embodiment, the present invention provides a novel compound of formula Ic, wherein:
R1 is selected from the group C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-8 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl and C1-4 alkoxy-C1-4 alkyl;
R1 is substituted with a C3-8 cycloalkyl group, wherein 0-1 carbon atoms in the C4-8 cycloalkyl group is replaced by a group selected from the group xe2x80x94Oxe2x80x94, xe2x80x94S(O)nxe2x80x94, xe2x80x94NR13axe2x80x94, xe2x80x94NCO2R14bxe2x80x94, xe2x80x94NCOR14bxe2x80x94 and xe2x80x94NSO2R14bxe2x80x94;
R1 is also substituted with 0-3 substituents independently selected at each occurrence from the group R1a, R1b, R1c, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94OR13a, xe2x80x94NR13aR16a, C1-2 alkoxy-C1-2 alkyl, and C3-8 cycloalkyl which is substituted with 0-1 R9 and in which 0-1 carbons of C4-8 cycloalkyl is replaced by xe2x80x94Oxe2x80x94;
provided that R1 is other than a cyclohexyl-(CH2)2xe2x80x94 group;
R1a is aryl and is selected from the group phenyl, naphthyl, indanyl and indenyl, each R1a being substituted with 0-1 xe2x80x94OR17 and 0-5 substituents independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94CN, nitro, SH, xe2x80x94S(O)nR18, xe2x80x94COR17, xe2x80x94OC(O)R18, xe2x80x94NR15aCOR17, xe2x80x94N(COR17)2, xe2x80x94NR15aCONR17aR19a, xe2x80x94NR15aCO2R18, xe2x80x94NR17aR19a, and xe2x80x94CONR17aR19a;
R1b is heteroaryl and is selected from the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-onyl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94CN, nitro, xe2x80x94OR17, SH, xe2x80x94S(O)mR18, xe2x80x94COR17, xe2x80x94OC(O)R18, xe2x80x94NR15aCOR17, xe2x80x94N(COR17)2, xe2x80x94NR15aCONR17aR19a, xe2x80x94NR15aCO2R18, xe2x80x94NR17aR19a, and xe2x80x94CONR17aR19a and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R15a, CO2R14b, COR14b and SO2R14b; and,
R1c is heterocyclyl and is a saturated or partially saturated heteroaryl, each heterocyclyl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94CN, nitro, xe2x80x94OR13a, SH, S(O)nR14b, xe2x80x94COR13a, xe2x80x94OC(O)R14b, xe2x80x94NR15aCOR13a, xe2x80x94N(COR13a)2, xe2x80x94NR15aCONR13aR16a, xe2x80x94NR15aCO2R14b, xe2x80x94NR13aR16a, and xe2x80x94CONR13aR16a and each heterocyclyl being substituted on any nitrogen atom with 0-1 substituents selected from the group R13a, CO2R14b, COR14b and SO2R14b and wherein any sulfur atom is optionally monooxidized or dioxidized.
[4r] In another even more preferred embodiment, the present invention provides a novel compound of formula Ic, wherein:
X is selected from the group O, S(O)n and a bond;
n is 0, 1 or 2;
R1 is selected from the group C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-8 cycloalkyl;
R1 is substituted with a C3-6 cycloalkyl group, wherein 0-1 carbon atoms in the C4-6 cycloalkyl group is replaced by a group selected from the group xe2x80x94Oxe2x80x94, xe2x80x94S(O)nxe2x80x94, and xe2x80x94NR13axe2x80x94;
R1 is also substituted with 0-2 substituents independently selected at each occurrence from the group R1a, R1b, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, Br, Cl, F, CF3, CF2CF3, xe2x80x94OR13a, xe2x80x94NR13aR16a, C1-2 alkoxy-C1-2 alkyl, and C3-6 cycloalkyl which is substituted with 0-1 R9 and in which 0-1 carbons of C4-8 cycloalkyl is replaced by xe2x80x94Oxe2x80x94;
R1a is aryl and is selected from the group phenyl and indanyl, each R1a being substituted with 0-1 xe2x80x94OR17 and 0-5 substituents independently selected at each occurrence from the group C1-4 alkyl, C3-6 cycloalkyl, Br, Cl, F, C1-4 haloalkyl, xe2x80x94CN, xe2x80x94S(O)nR18, xe2x80x94COR17, xe2x80x94NR17aR19a, and xe2x80x94CONR17aR19a;
R1b is heteroaryl and is selected from the group pyridyl, pyrimidinyl, furanyl, thienyl, imidazolyl, thiazolyl, pyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, and indazolyl, each heteroaryl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-4 alkyl, C3-6 cycloalkyl, Br, Cl, F, CF3, xe2x80x94CN, xe2x80x94OR17, xe2x80x94S(O)mR18, xe2x80x94COR17, xe2x80x94NR17aR19a, and xe2x80x94CONR17aR19a and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R15a, CO2R14b, COR14b and SO2R14b;
R2 is selected from the group C1-4 alkyl, C2-4 alkenyl, and C2-4 alkynyl and is substituted with 0-1 substituents selected from the group xe2x80x94CN, OH, Cl, F, and C1-4 alkoxy;
R9 is independently selected at each occurrence from the group H, C1-4 alkyl and C3-8 cycloalkyl;
R3 is selected from the group H, Br, Cl, F, xe2x80x94CN, C1-4 alkyl, C3-6 cycloalkyl, C1-4 alkoxy, NH2, C1-4 alkylamino, and (C1-4 alkyl)2-amino;
R13 is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, C3-6 cycloalkyl-C1-2 alkyl, aryl(C1-2 alkyl)-, and heteroaryl(C1-2 alkyl)-;
R13a and R16a are independently selected at each occurrence from the group H, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-C1-6 alkyl;
R14 is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, C3-6 cycloalkyl-C1-2 alkyl, aryl(C1-2 alkyl)-, and heteroaryl(C1-2 alkyl)-;
R14a is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, and C3-6 cycloalkyl-C1-2 alkyl;
R14b is selected from the group C1-4 alkyl, C1-2 haloalkyl, C1-2 alkoxy-C1-2 alkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-C1-2 alkyl;
R15 is independently selected at each occurrence from the group H, C1-4 alkyl, C3-7 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, phenyl and benzyl, each phenyl or benzyl being substituted on the aryl moiety with 0-3 groups chosen from the group C1-4 alkyl, Br, Cl, F, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and dimethylamino;
R15a is independently selected at each occurrence from the group H, C1-4 alkyl, C3-7 cycloalkyl, and C3-6 cycloalkyl-C1-6 alkyl;
R17, R18 and R19 are independently selected at each occurrence from the group H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, C1-2 alkoxy-C1-2 alkyl, and C1-4 haloalkyl;
alternatively, in an NR17R19 moiety, R17 and R19 taken together form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N4 in 1-piperazinyl is substituted with 0-1 substituents selected from the group R13, CO2R14, COR14 and SO2R14;
R17a and R19a are independently selected at each occurrence from the group H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl and C1-4 haloalkyl;
aryl is phenyl substituted with 1-4 substituents independently selected at each occurrence from the group C1-4 alkyl, C3-6 cycloalkyl, xe2x80x94OR17, Br, Cl, F, C1-4 haloalkyl, xe2x80x94CN, xe2x80x94S(O)nR18, xe2x80x94COR17, xe2x80x94CO2R17, xe2x80x94NR15COR17, xe2x80x94NR15CO2R18, xe2x80x94NR17R19, and xe2x80x94CONR17R19; and,
heteroaryl is independently selected at each occurrence from the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-on-yl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted 1-4 carbon atoms with a substituent independently selected at each occurrence from the group C16 alkyl, C3-6 cycloalkyl, Br, Cl, F, C1-4 haloalkyl, xe2x80x94CN, xe2x80x94OR17, xe2x80x94S(O)mR18, xe2x80x94COR17, xe2x80x94CO2R17, xe2x80x94OC(O)R18, xe2x80x94NR15COR17, xe2x80x94N(COR17)2, xe2x80x94NR15CO2R18, xe2x80x94NR17R19, and xe2x80x94CONR17R19 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R15, CO2R14a, COR14a and SO2R14a.
[4s] In another still more preferred embodiment, the present invention provides a novel compound of formula Ic, wherein:
X is selected from the group O, S and a bond;
R1 is C1-6 alkyl;
R1 is substituted with a C3-6 cycloalkyl, wherein 0-1 carbon atoms in the C4-4 cycloalkyl is replaced by a group selected from the group xe2x80x94Oxe2x80x94, xe2x80x94S(O)nxe2x80x94, and xe2x80x94NR13axe2x80x94;
R1 is also substituted with 0-2 substituents independently selected at each occurrence from the group R1a, R1b, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, F, CF3, xe2x80x94OR13a, xe2x80x94NR13aR16a, xe2x80x94CH2OCH3, xe2x80x94CH2CH2OCH3, and C3-6 cycloalkyl which is substituted with 0-1 CH3 and in which 0-1 carbons of C4-8 cycloalkyl is replaced by xe2x80x94Oxe2x80x94;
provided that R1 is other than a cyclohexyl-(CH2)2xe2x80x94 group;
R1a is aryl and is phenyl substituted with 0-1 substituents selected from OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, and OCF3, and 0-3 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, Br, Cl, F, CF3, xe2x80x94CN, SCH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2;
R1b is heteroaryl and is selected from the group furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, and indazolyl, each heteroaryl being substituted on 0-3 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH3, CO2CH3, COCH3 and SO2CH3;
R2 is selected from the group CH3, CH2CH3, CH(CH3)2, and CH2CH2CH3;
R3 is selected from the group H, CH3, CH2CH3, CH(CH3)2, and CH2CH2CH3;
aryl is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, SO2CH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2; and,
heteroaryl is independently selected at each occurrence from the group pyridyl, indolyl, benzothienyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, and benzoxazolin-2-on-yl, each heteroaryl being substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, SO2CH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH3, CO2CH3, COCH3 and SO2CH3.
[4t] In another further preferred embodiment, the present invention provides a novel compound of formula Ic, wherein:
R1 is (cyclopropyl)C1 alkyl or (cyclobutyl)C1 alkyl;
R1 is substituted with 1-2 substituents independently selected at each occurrence from the group R1a, R1b, CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, xe2x80x94(CH2)3CH3, xe2x80x94CHxe2x95x90CH2; xe2x80x94CHxe2x95x90CH(CH3), xe2x80x94CHxe2x89xa1CH, xe2x80x94CHxe2x89xa1C(CH3), xe2x80x94CH2OCH3, xe2x80x94CH2CH2OCH3, F, CF3, cyclopropyl, CH3-cyclopropyl, cyclobutyl, CH3-cyclobutyl, cyclopentyl, CH3-cyclopentyl;
R1a is phenyl substituted with 0-1 substituents selected from OCH3, OCH2CH3, and OCF3, and 0-2 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, Br, Cl, F, CF3, xe2x80x94CN, and SCH3;
R1b is heteroaryl and is selected from the group furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, and tetrazolyl, each heteroaryl being substituted on 0-3 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, OCH3, OCH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, and SCH3 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH3, CO2CH3, COCH3 and SO2CH3;
R2 is selected from the group CH3, CH2CH3, and CH(CH3)2;
R3 is selected from the group H and CH3;
aryl is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, SO2CH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2; and,
heteroaryl is pyridyl substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, SCH3, SO2CH3, xe2x80x94NH2, xe2x80x94NHCH3, xe2x80x94N(CH3)2, xe2x80x94C(O)NH2, xe2x80x94C(O)NHCH3, and xe2x80x94C(O)N(CH3)2.
[4u] In another even further preferred embodiment, the present invention provides a novel compound of formula Ic, wherein:
R1 is (cyclopropyl)C1 alkyl or (cyclobutyl)C1 alkyl;
R1 is substituted with 1-2 substituents independently selected at each occurrence from the group R1a, R1b, CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, xe2x80x94(CH2)3CH3, xe2x80x94CHxe2x95x90CH2, xe2x80x94CHxe2x95x90CH(CH3), xe2x80x94CHxe2x89xa1CH, xe2x80x94CHxe2x89xa1C(CH3), xe2x80x94CH2OCH3, xe2x80x94CH2CH2OCH3, F, CF3, cyclopropyl, and CH3-cyclopropyl;
R1a is phenyl substituted with 0-2 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, Br, Cl, F, CF3, xe2x80x94CN, and SCH3;
R1b is heteroaryl and is selected from the group furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, and pyrazolyl, each heteroaryl being substituted on 0-3 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, OCH3, OCH2CH3, OCF3, Br, Cl, F, CF3, xe2x80x94CN, and SCH3.
[4v] In another further preferred embodiment, the present invention provides a novel compound of formula Ic, wherein:
D is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, and CF3.
[4w] In another further preferred embodiment, the present invention provides a novel compound of formula Ic, wherein:
D is pyridyl substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, cyclopropyl, OCH3, OCH2CH3, OCH(CH3)2, OCH2CH2CH3, OCF3, Br, Cl, F, and CF3.
[5] In a third embodiment, the present invention provides a novel pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I): 
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:
A is N or Cxe2x80x94R7;
B is N or Cxe2x80x94R8;
provided that at least one of the groups A and B is N;
D is an aryl or heteroaryl group attached through an unsaturated carbon atom;
X is selected from the group CHxe2x80x94R9, Nxe2x80x94R10, O, S(O)n and a bond;
n is 0, 1 or 2;
R1 is selected from the group C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-8 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, C1-4 alkoxy-C1-4 alkyl, xe2x80x94SO2xe2x80x94C1-10 alkyl, xe2x80x94SO2xe2x80x94R1a, and xe2x80x94SO2xe2x80x94R1b;
R1 is substituted with 0-1 substituents selected from the group xe2x80x94CN, xe2x80x94S(O)nR14b, xe2x80x94COR13a, xe2x80x94CO2R13a, xe2x80x94NR15aCOR13a, xe2x80x94N(COR13a)2, xe2x80x94NR15aCONR13aR16a, xe2x80x94NR15aCO2R14b, xe2x80x94CONR13aR16a, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, and C3-8 cycloalkyl, wherein 0-1 carbon atoms in the C4-8 cycloalkyl is replaced by a group selected from the group xe2x80x94Oxe2x80x94, xe2x80x94S(O)nxe2x80x94, xe2x80x94NR13a, xe2x80x94NCO2R14b, xe2x80x94NCOR14bxe2x80x94 and xe2x80x94NSO2R14bxe2x80x94, and wherein N4 in 1-piperazinyl is substituted with 0-1 substituents selected from the group R13a, CO2R14b, COR14b and SO2R14b;
R1 is also substituted with 0-3 substituents independently selected at each occurrence from the group R1a, R1b, R1c, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94OR13a, xe2x80x94NR13aR16a, and C3-8 cycloalkyl which is substituted with 0-1 R9 and in which 0-1 carbons of C4-8 cycloalkyl is replaced by xe2x80x94Oxe2x80x94;
provided that R1 is other than:
(a) a 3-cyclopropyl-3-methoxypropyl group;
(b) an unsubstituted-(alkoxy)methyl group; and,
(c) a 1-hydroxyalkyl group;
also provided that when R1 alkyl substituted with OH, then the carbon adjacent to the ring N is other than CH2;
R1a is aryl and is selected from the group phenyl, naphthyl, indanyl and indenyl, each R1a being substituted with 0-5 substituents independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94CN, nitro, xe2x80x94OR17, SH, xe2x80x94S(O)nR18, xe2x80x94COR17, xe2x80x94OC(O)R18, xe2x80x94NR15aCOR17, xe2x80x94N(COR17)2, xe2x80x94NR15aCONR17aR19a, xe2x80x94NR15aCO2R18, xe2x80x94NR17aR19a, and xe2x80x94CONR17aR19a;
R1b is heteroaryl and is selected from the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-onyl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94CN, nitro, xe2x80x94OR17, SH, xe2x80x94S(O)mR18, xe2x80x94COR17, xe2x80x94OC(O)R18, xe2x80x94NR15aCOR17, xe2x80x94N(COR17)2, xe2x80x94NR15aCONR17aR19a, xe2x80x94NR15aCO2R18, xe2x80x94NR17aR19a, and xe2x80x94CONR17aR19a and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R15a, CO2R14b, COR14b and SO2R14b;
R1c is heterocyclyl and is a saturated or partially saturated heteroaryl, each heterocyclyl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94CN, nitro, xe2x80x94OR13a, SH, xe2x80x94S(O)nR14b, xe2x80x94COR13a, xe2x80x94OC(O)
R14b, xe2x80x94NR15aCOR13a, xe2x80x94N(COR13a)2, xe2x80x94NR15aCONR13aR16a, xe2x80x94NR15aCO2R14b, xe2x80x94NR13aR16a, and xe2x80x94CONR13aR16a and each heterocyclyl being substituted on any nitrogen atom with 0-1 substituents selected from the group R13a, CO2R14b, COR14b and SO2R14b and wherein any sulfur atom is optionally monooxidized or dioxidized;
R2 is selected from the group C1-4 alkyl, C3-8 cycloalkyl, C2-4 alkenyl, and C2-4 alkynyl and is substituted with 0-3 substituents selected from the group xe2x80x94CN, hydroxy, halo and C1-4 alkoxy;
alternatively R2, in the case where X is a bond, is selected from the group xe2x80x94CN, CF3 and C2F5;
R3, R7 and R8 are independently selected at each occurrence from the group H, Br, Cl, F, I, xe2x80x94CN, C1-4 alkyl, C3-8 cycloalkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylsulfinyl, C1-4 alkylsulfonyl, amino, C1-4 alkylamino, (C1-4 alkyl)2amino and phenyl, each phenyl is substituted with 0-3 groups selected from the group C1-7 alkyl, C3-8 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, nitro, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 alkylthio, C1-4 alkyl sulfinyl, C1-4 alkylsulfonyl, C1-6 alkylamino and C1-4 alkyl)2amino;
provided that when R1 is unsubstituted C1-10 alkyl, then R3 is other than substituted or unsubstituted phenyl;
R9 and R10 are independently selected at each occurrence from the group H, C1-4 alkyl, C3-6 cycloalkyl-C1-4 alkyl and C3-8 cycloalkyl;
R13 is selected from the group H, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, aryl, aryl(C1-4 alkyl)-, heteroaryl and heteroaryl (C1-4 alkyl)-;
R13a and R16a are independently selected at each occurrence from the group H, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-C1-6 alkyl;
R14 is selected from the group C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, aryl, aryl(C1-4 alkyl)-, heteroaryl and heteroaryl(C1-4 alkyl)- and benzyl, each benzyl being substituted on the aryl moiety with 0-1 substituents selected from the group C1-4 alkyl, Br, Cl, F, I, C1-4 haloalkyl, nitro, C1-4 alkoxy C1-4 haloalkoxy, and dimethylamino;
R14a is selected from the group C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl and benzyl, each benzyl being substituted on the aryl moiety with 0-1 substituents selected from the group C1-4 alkyl, Br, Cl, F, I, C1-4 haloalkyl, nitro, C1-4 alkoxy, C1-4 haloalkoxy, and dimethylamino;
R14b is selected from the group C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-C1-6 alkyl;
R15 is independently selected at each occurrence from the group H, C1-4 alkyl, C3-7 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, phenyl and benzyl, each phenyl or benzyl being substituted on the aryl moiety with 0-3 groups chosen from the group C1-4 alkyl, Br, Cl, F, I, C1-4 haloalkyl, nitro, C1-4 alkoxy, C1-4 haloalkoxy, and dimethylamino;
R15a is independently selected at each occurrence from the group H, C1-4 alkyl, C3-7 cycloalkyl, and C3-6 cycloalkyl-C1-6 alkyl;
R17 is selected at each occurrence from the group H, C1-6 alkyl, C3-10 cycloalkyl, cycloalkyl-C3-6 alkyl, C1-2 alkoy-C1-2 alkyl, C1-4 haloalkyl, R14S(O)nC1-4 alkyl, and R17bR19bNxe2x80x94C2-4 alkyl;
R18 and R19 are independently selected at each occurrence from the group H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, C1-2 alkoxy-C1-2 alkyl, and C1-4 haloalkyl;
alternatively, in an NR17R19 moiety, R17 and R19 taken together form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N4 in 1-piperazinyl is substituted with 0-1 substituents selected from the group R13, CO2R14, COR14 and SO2R14;
alternatively, in an NR17bR19b moiety, R17b and R19b taken together form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N4 in 1-piperazinyl is substituted with 0-1 substituents selected from the group R13, CO2R14, COR14 and SO2R14;
R17a and R19a are independently selected at each occurrence from the group H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl and C1-4 haloalkyl;
aryl is independently selected at each occurrence from the group phenyl, naphthyl, indanyl and indenyl, each aryl being substituted with 0-5 substituents independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, methylenedioxy, C1-4 alkoxy-C1-4 alkoxy, xe2x80x94OR17, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94CN, xe2x80x94NO2, SH, xe2x80x94S(O)nR18, xe2x80x94COR17, xe2x80x94CO2R17, xe2x80x94OC(O)R18, xe2x80x94NR15COR17, xe2x80x94N(COR17)2, xe2x80x94NR15CONR17R19, xe2x80x94NR15CO2R18, xe2x80x94NR17R19, and xe2x80x94CONR17R19 and up to 1 phenyl, each phenyl substituent being substituted with 0-4 substituents selected from the group C1-3 alkyl, C1-3 alkoxy, Br, Cl, F, I, xe2x80x94CN, dimethylamino, CF3, C2F5, OCF3, SO2Me and acetyl; and,
heteroaryl is independently selected at each occurrence from the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-on-yl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94CN, nitro, xe2x80x94OR17, SH, xe2x80x94S(O)mR18, xe2x80x94COR17, xe2x80x94CO2R17, xe2x80x94OC(O)R18, xe2x80x94NR15COR17, xe2x80x94N(COR17)2, xe2x80x94NR15CONR17R19, xe2x80x94NR15CO2R18, xe2x80x94NR17R19, and xe2x80x94CONR17R19 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R15, CO2R14a, COR14a and SO2R14a.
[6] In a second embodiment, the present invention provides a novel method of treating affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer""s disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, in mammals, comprising: administering to the mammal a therapeutically effective amount of a compound of formula (I): 
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:
A is N or Cxe2x80x94R7;
B is N or Cxe2x80x94R8; provided that at least one of the groups A and B is N;
D is an aryl or heteroaryl group attached through an unsaturated carbon atom;
X is selected from the group CHxe2x80x94R9, Nxe2x80x94R10, O, S(O)n and a bond;
n is 0, 1 or 2;
R1 is selected from the group C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-8 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, C1-4 alkoxy-C1-4 alkyl, xe2x80x94SO2xe2x80x94C1-10 alkyl, xe2x80x94SO2xe2x80x94R1a, and xe2x80x94SO2xe2x80x94R1b;
R1 is substituted with 0-1 substituents selected from the group xe2x80x94CN, xe2x80x94S(O)nR14b, xe2x80x94COR13a, xe2x80x94CO2R13a, xe2x80x94NR15aCOR13a, xe2x80x94N(COR13a)2, xe2x80x94NR15aCONR13aR16a, xe2x80x94NR15aCO2R14b, xe2x80x94CONR13aR16a, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, and C3-8 cycloalkyl, wherein 0-1 carbon atoms in the C4-8 cycloalkyl is replaced by a group selected from the group xe2x80x94Oxe2x80x94, xe2x80x94S(O)nxe2x80x94, xe2x80x94NR13axe2x80x94, xe2x80x94NCO2R14bxe2x80x94, xe2x80x94NCOR14bxe2x80x94 and xe2x80x94NSO2R14bxe2x80x94, and wherein N4 in 1-piperazinyl is substituted with 0-1 substituents selected from the group R13a, CO2R14b, COR14b and SO2R14b;
R1 is also substituted with 0-3 substituents independently selected at each occurrence from the group R1a, R1b, R1c, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94OR13a, xe2x80x94NR13aR16a, and C3-8 cycloalkyl which is substituted with 0-1 R9 and in which 0-1 carbons of C4-8 cycloalkyl is replaced by xe2x80x94Oxe2x80x94;
provided that R1 is other than:
(a) a 3-cyclopropyl-3-methoxypropyl group;
(b) an unsubstituted-(alkoxy)methyl group; and,
(c) a 1-hydroxyalkyl group;
also provided that when R1 alkyl substituted with OH, then the carbon adjacent to the ring N is other than CH2;
R1a is aryl and is selected from the group phenyl, naphthyl, indanyl and indenyl, each R1a being substituted with 0-5 substituents independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94CN, nitro, xe2x80x94OR17, SH, xe2x80x94S(O)nR18, xe2x80x94COR17, xe2x80x94OC(O)R18, xe2x80x94NR15aCOR17, xe2x80x94N(COR17)2, xe2x80x94NR15aCONR17aR19a, xe2x80x94NR15aCO2R18, xe2x80x94NR17aR19a, and xe2x80x94CONR17aR19a;
R1b is heteroaryl and is selected from the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-onyl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94CN, nitro, xe2x80x94OR17, SH, xe2x80x94S(O)mR18, xe2x80x94COR17, xe2x80x94OC(O)R18, xe2x80x94NR15aCOR17, xe2x80x94N(COR17)2, xe2x80x94NR15aCONR17aR19a, xe2x80x94NR15aCO2R18, xe2x80x94NR17aR19a, and xe2x80x94CONR17aR19a and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R15a, CO2R14b, COR14b and SO2R14b;
R1c is heterocyclyl and is a saturated or partially saturated heteroaryl, each heterocyclyl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94CN, nitro, xe2x80x94OR13a, SH, S(O)nR14b, xe2x80x94COR13a, xe2x80x94OC(O) R14b, xe2x80x94NR15aCOR13a, xe2x80x94N(COR13a)2, xe2x80x94NR15aCONR13aR16a, xe2x80x94NR15aCO2R14b, xe2x80x94NR13aR16a, and xe2x80x94CONR13aR16a and each heterocyclyl being substituted on any nitrogen atom with 0-1 substituents selected from the group R13a, CO2R14b, COR14b and SO2R14b and wherein any sulfur atom is optionally monooxidized or dioxidized;
R2 is selected from the group C1-4 alkyl, C3-8 cycloalkyl, C2-4 alkenyl, and C2-4 alkynyl and is substituted with 0-3 substituents selected from the group xe2x80x94CN, hydroxy, halo and C1-4 alkoxy;
alternatively R2, in the case where X is a bond, is selected from the group xe2x80x94CN, CF3 and C2F5;
R3, R7 and R8 are independently selected at each occurrence from the group H, Br, Cl, F, I, xe2x80x94CN, C1-4 alkyl, C3-8 cycloalkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylsulfinyl, C1-4 alkylsulfonyl, amino, C1-4 alkylamino, (C1-4 alkyl)2amino and phenyl, each phenyl is substituted with 0-3 groups selected from the group C1-7 alkyl, C3-8 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, nitro, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 alkylthio, C1-4 alkyl sulfinyl, C1-4 alkylsulfonyl, C1-6 alkylamino and (C1-4 alkyl)2amino;
provided that when R1 is unsubstituted C1-10 alkyl, then R3 is other than substituted or unsubstituted phenyl;
R9 and R10 are independently selected at each occurrence from the group H, C1-4 alkyl, C3-6 cycloalkyl-C1-4 alkyl and C3-8 cycloalkyl;
R13 is selected from the group H, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, aryl, aryl(C1-4 alkyl)-, heteroaryl and heteroaryl(C1-4 alkyl)-;
R13a and R16a are independently selected at each occurrence from the group H, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-C1-6 alkyl;
R14 is selected from the group C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, aryl, aryl(C1-4 alkyl)-, heteroaryl and heteroaryl(C1-4 alkyl)- and benzyl, each benzyl being substituted on the aryl moiety with 0-1 substituents selected from the group C1-4 alkyl, Br, Cl, F, I, C1-4 haloalkyl, nitro, C1-4 alkoxy C1-4 haloalkoxy, and dimethylamino;
R14a is selected from the group C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl and benzyl, each benzyl being substituted on the aryl moiety with 0-1 substituents selected from the group C1-4 alkyl, Br, Cl, F, I, C1-4 haloalkyl, nitro, C1-4 alkoxy, C1-4 haloalkoxy, and dimethylamino;
R14bis selected from the group C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy-C1-4 alkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-C1-6 alkyl;
R15 is independently selected at each occurrence from the group H, C1-4 alkyl, C3-7 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, phenyl and benzyl, each phenyl or benzyl being substituted on the aryl moiety with 0-3 groups chosen from the group C1-4 alkyl, Br, Cl, F, I, C1-4 haloalkyl, nitro, C1-4 alkoxy, C1-4 haloalkoxy, and dimethylamino;
R15a is independently selected at each occurrence from the group H, C1-4 alkyl, C3-7 cycloalkyl, and C3-6 cycloalkyl-C1-6 alkyl;
R17 is selected at each occurrence from the group H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, C1-2 alkoxy-C1-2 alkyl, C1-4 haloalkyl, R14S(O)nxe2x80x94C1-4 alkyl, and R17bR19bNxe2x80x94C2-4 alkyl;
R18 and R19 are independently selected at each occurrence from the group H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl, C1-2 alkoxy-C1-2 alkoyl, and C1-4 haloalkyl;
alternatively, in an NR19R19 moiety, R17 and R19 taken together form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N4 in 1-piperazinyl is substituted with 0-1 substituents selected from the group R13, CO2R14, COR14 and SO2R14;
alternatively, in an NR17bR19b moiety, R17b and R19b taken together form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperaziinyl, wherein N4 in 1-piperazinyl is substituted with 0-1 substituents selected from the group R13, CO2R14, CR14 and SOR14;
R17a and R19a are independently selected at each occurrence from the group H, C1-6 alkyl, C3-10 cycloalkyl, C3-6 cycloalkyl-C1-6 alkyl and C1-4 haloalkyl;
aryl is independently selected at each occurrence from the group phenyl, naphthyl, indanyl and indenyl, each aryl being substituted with 0-5 substituents independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, methylenedioxy, C1-4 alkoxy-C1-4 alkoxy, xe2x80x94OR17, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94CN, xe2x80x94NO2, SH, xe2x80x94S(O)nR18, xe2x80x94COR17, xe2x80x94CO2R17, xe2x80x94OC(O)R18, xe2x80x94NR15COR17, xe2x80x94N(COR17)2, xe2x80x94NR15CONR17R19, xe2x80x94NR15CO2R18, xe2x80x94NR17R19, and xe2x80x94CONR17R19 and up to 1 phenyl, each phenyl substituent being substituted with 0-4 substituents selected from the group C1-3 alkyl, C1-3 alkoxy, Br, Cl, F, I, xe2x80x94CN, dimethylamino, CF3, C2F5, OCF3, SO2Me and acetyl; and,
heteroaryl is independently selected at each occurrence from the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-on-yl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C1-6 alkyl, C3-6 cycloalkyl, Br, Cl, F, I, C1-4 haloalkyl, xe2x80x94CN, nitro, xe2x80x94OR17, SH, xe2x80x94S(O)mR18, xe2x80x94COR17, xe2x80x94CO2R17, xe2x80x94OC(O)R18, xe2x80x94NR15COR17, xe2x80x94N(COR17)2, xe2x80x94NR15CONR17R19, xe2x80x94NR15CO2R18, xe2x80x94NR17R19, and xe2x80x94CONR17R19 and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R15, CO2R14a, COR14a and SO2R14a.
In another preferred embodiment, R1 is other than a cyclohexyl-(CH2)1, 2, 3, 4, 5, 6, 7, 8, 9, or 10xe2x80x94 group.
In another preferred embodiment, R1 is other than an aryl-(CH2)1, 2, 3, 4, 5, 6, 7, 8, 9, or 10xe2x80x94 group, wherein the aryl group is substituted or unsubstituted.
In another preferred embodiment, R1 is other than a heteroaryl-(CH2)1, 2, 3, 4, 5, 6, 7, 8, 9, or 10xe2x80x94 group, wherein the heteroaryl group is substituted or unsubstituted.
In another preferred embodiment, R1 is other than a heterocyclyl-(CH2)1, 2, 3, 4, 5, 6, 7, 8, 9, or 10xe2x80x94 group, wherein the heterocyclyl group is substituted or unsubstituted.
In another preferred embodiment, when D is imidazole or triazole, R1 is other than unsubstituted C1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 linear or branched alkyl or C3, 4, 5, 6, 7, or 8 cycloalkyl.
In another preferred embodiment, R1a is not substituted with OR17.
Many compounds of this invention have one or more asymmetric centers or planes. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are included in the present invention. Many geometric isomers of olefins, Cxe2x95x90N double bonds, and the like can also be present in the compounds, and all such stable isomers are contemplated in the present invention. The compounds may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. All chiral, (enantiomeric and diastereomeric) and racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.
The term xe2x80x9calkylxe2x80x9d includes both branched and straight-chain alkyl having the specified number of carbon atoms. xe2x80x9cAlkenylxe2x80x9d includes hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like. xe2x80x9cAlkynylxe2x80x9d includes hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl and the like. xe2x80x9cHaloalkylxe2x80x9d is intended to include both branched and straight-chain alkyl having the specified number of carbon atoms, substituted with 1 or more halogen; xe2x80x9calkoxyxe2x80x9d represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge; xe2x80x9ccycloalkylxe2x80x9d is intended to include saturated ring groups, including mono-,bi- or poly-cyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and so forth. xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d includes fluoro, chloro, bromo, and iodo.
The term xe2x80x9csubstitutedxe2x80x9d, as used herein, means that one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., xe2x95x90O), then 2 hydrogens on the atom are replaced.
Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By xe2x80x9cstable compoundxe2x80x9d or xe2x80x9cstable structurexe2x80x9d is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d includes acid or base salts of the compounds of formulas (I) and (II). Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
Pharmaceutically acceptable salts of the compounds of the invention can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
xe2x80x9cProdrugsxe2x80x9d are considered to be any covalently bonded carriers which release the active parent drug of formula (I) or (II) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds of formula (I) and (II) are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds wherein hydroxy, amine, or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formulas (I) and (II); and the like.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d of a compound of this invention means an amount effective to antagonize abnormal level of CRF or treat the symptoms of affective disorder, anxiety, depression, immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress in a host.
Compounds of formula (I) can be prepared by the following synthetic routes and schemes. Where a detailed description is not provided, it is assumed that those skilled in the art of organic synthesis will readily understand the meaning.
Synthesis of compounds of formula (I) may be prepared by the reaction shown in Scheme 1. 
A compound of formula (II) can be alkylated on the imidazole nitrogen atom with an appropriate reagent. Typical conditions for this transformation include treatment of compound (II) with a base, such as sodium hydride, potassium tert-butoxide, sodium hexamethyldisilazide, etc., followed by a reagent Jxe2x80x94R1, where J represents a halide (chloride, bromide or iodide) or psuedohalide (tosylate, mesylate, triflate, etc.), at an appropriate temperature (0xc2x0 C. or room temperature, with warming if necessary) in a solvent such as tetrahydrofuran, dimethylformamide or dimethylsulfoxide. Alternatively, this reaction may be performed using the Mitsunobu conditions (Mitsunobu, Synthesis 1981, pp. 1-28). The compound (II) is treated with an alcohol compound R1OH, along with a phosphine (triphenyl, tributyl, etc.) and a phosphine-activating reagent such as diethyl azodicarboxylate.
Compounds of Formula (II) may be prepared according to the route shown in Scheme 2. 
A compound of Formula (III) may be coupled to an aromatic compound of Formula (IV), with elimination of the elements of Mxe2x80x94K. For compound (III), K represents a halide, psuedohalide (such as mesylate, tosylate or triflate), or thiomethyl, and P represents a protecting group (if the conditions of the reaction warrant protection of the imidazole Nxe2x80x94H; otherwise, P can be H). Suitable P groups may include benzyl, 4-methoxybenzyl, methoxymethyl, trimethylsilylethoxymethyl, tert-butoxycarbonyl or benzyloxycarbonyl. For compound (IV), M represents groups such as lithium, bromomagnesium, chlorozinc, (dihydroxy)boron, (dialkoxy)boron, trialkylstannyl and the like. The coupling reaction may be performed in the presence of an appropriate catalyst, such as tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, [1,3-bis(diphenylphosphino)propane]nickel dichloride, etc. Two particularly useful methods involve the coupling of chloroheterocycles with in-situ-prepared arylzinc reagents according to the method of Negishi et al. (J. Org. Chem. 1977, 42, 1821), and the coupling with arylboronic esters according to the method of Suzuki et al. (Chem. Letters 1989, 1405). Appropriate solvents for reactions of this type usually include tetrahydrofuran, diethyl ether, dimethylformamide, or dimethylsulfoxide. Typical temperatures range from ambient up to the boiling point of the solvent. Once coupled, the P group may be removed to afford compound (II). Conditions for the removal of the protecting groups are well known to those familiar to the art of organic synthesis; e.g. hydrogenation to remove benzyl or benzyloxycarbonyl, a fluoride source (such as tetrabutylammonium fluoride) to remove silylethoxymethyl, an acid source (such as trifluoroacetic acid) to remove tert-butoxycarbonyl or 4-methoxybenzyl, etc.
Compounds of formula (III) can be prepared according to the plan shown in Scheme 3. 
A diamine compound of formula (V) (in this case, P is a group such as benzyl, which can be introduced already attached to the nitrogen atom; otherwise, P could represent H initially, and another protecting group being introduced in a later step) is used in a cyclocondensation reaction to make the imidazole ring. The conditions used will, of course, depend on the X group chosen, and may include the intermediacy of the compound (VI). A review of imidazole-forming reactions may be found in Comprehensive Heterocyclic Chemistry (Pergamon Press, 1984) vol. 5, pp. 457-498.
Preparation of compounds of formula (V) wherein both A and B are nitrogen atoms may proceed according to the route of Scheme 4. 
A compound of formula (VII) may be available from commercial sources, particularly for K=chloride. Compounds bearing psuedohalide K groups may be available from the corresponding dihydroxy compounds by treatment with an appropriate activating reagent, such as an organosulfonic anhydride or sulfonyl chloride. Compound (VII) may be converted to (V) by either (i) monoalkylation with a compound Pxe2x80x94NH2, followed by reduction of the nitro group; (ii) reduction of the nitro group, to give an amine compound of formula (VIII), followed by monoalkylation with a compound Pxe2x80x94NH2; or (iii) use of a source of ammonia (ammonia gas, ammonium hydroxide, etc.) in either route, followed by protection of the amine group with the group P. Pyrimidine chemistry of this type is well represented in the literature, and is reviewed in Comprehensive Heterocyclic Chemistry, vol. 6. Alkylation of chloropyrimidines with amine compounds can be accomplished under either acidic (e.g. HCl or acetic) or basic (trialkylamines, potassium tert-butoxide, etc.) conditions. Nitro groups in compounds of this type can be reduced to amino groups using one of any number of conditions, including catalytic hydrogenation, tin dichloride, sodium dithionite, zinc metal, iron powder, etc.
Preparation of compounds of formula (V) wherein either A or B represent nitrogen atoms is shown in Scheme 5. 
An hydroxypyridone compound of formula (IX) can be nitrated to give compound (X) employing conditions such as concentrated or fuming nitric acid, optionally in the presence of concentrated sulfuric or acetic acid. The hydroxypyridone can be selectively monoactivated with a K group to give a compound of formula (XI); one method to do this involves treatment of the dicyclohexylamine salt of compound (X) with phosphorus oxychloride to give (XI) wherein Kxe2x95x90Cl. Alternatively, both the hydroxy and pyridone groups in compound (X) can be activated at the same time, using stronger conditions such as phosphorus oxychloride and heat, or excess toluenesulfonic anhydride, to give compound (XII). Compound (XI) may be converted to the protected amine compound (XIII) using the same general route discussed above for the pyrimidines. Selective monoalkylation using compound (XII) is also possible, but will probably give mixtures of regioisomeric products (XIV) and (XV). The nitro groups in these compounds can then be reduced as discussed above, to give compounds for formula (V) wherein either A or B is nitrogen.
An alternative approach to the method involving introduction of the R1 group at the initial step is shown in Scheme 6. 
This is particularly useful in the cases where R1 represents a group where alkylation of compound (II) is impractical (e.g. a very bulky R1 group), but can also be used in a general manner. Here, compounds of formula (XVI) or (XVII) (either amino- or nitro-pyridines or pyrimidines) are alkylated with an amine reagent R1xe2x80x94NH2, under either acidic or basic conditions as described above. Nitro compound (XVIII) can be converted to amine compound (XIX) by nitro reduction reactions described earlier. Compound (XIX) can be cyclized to imidazole compound (XX). As above, this reaction will depend upon the choice of X group. For example, for Xxe2x95x90CHR9, one can use an orthoester reagent such as R2CH(R9)C(OR)3, with heating in neat solution or high-boiling solvents, and the optional presence of an acid catalyst (such as hydrochloric or sulfuric acid) (see Montgomery and Temple, J. Org. Chem. 1960, 25, 395). For Xxe2x95x90NR10, the cyclization is performed using reagents such as an guanidine reagent of the structure R2R10Nxe2x80x94C(xe2x95x90NH)NH2 or a urea-derived reagent of the structure R2R10Nxe2x80x94C(xe2x95x90NH)D, where D represents a group like OCH3, SCH3 or SO2CH3. For Xxe2x95x90O, the ring is formed using a reagent of the structure (R2O)4C (with acetic acid catalysis), provided one has access to the reagent with the R2 group of choice (see Brown and Lynn, J. Chem. Soc. Perkin Trans. I 1974, 349). Alternatively, the diamine (XIX) is treated with phosgene, followed by O-alkylation to introduce the R2 group (such as a reagent like R2xe2x80x94I or R2xe2x80x94Br). A similar route can be used for Xxe2x95x90S, which would use thiophosgene or some similar reagent, followed by S-alkylation with the R2 group. The sulfur atom in this compound (and sulfide groups throughout the molecule in general) can be oxidized to either the sulfoxide or sulfone if desired by treatment with an appropriate oxidizing agent such as potassium permanganate, potassium peroxomonosulfate or m-chloroperbenzoic acid. Finally, compound (XX) can be used in an aryl coupling reaction as described above to replace the K group with the desired aryl group in compound (I). Methods of synthesis of compounds R1xe2x80x94OH, R1xe2x80x94J and R1xe2x80x94NH2 are related, in that the alcohol can be used in the synthesis of the other two compounds, as is shown in Scheme 7. 
For example, the hydroxy group may be converted to the following J groups, using the indicated reagents (this route is not limited to these J groups): methanesulfonate, using methanesulfonyl chloride or anhydride and an appropriate base; toluenesulfonate, using toluenesulfonyl chloride or anhydride and an appropriate base; iodide; using iodine/triphenylphosphine; bromide, using phosphorus tribromide or carbon tetrabromide/triphenylphosphine; or trifluoromethanesulfonate, using trifluoromethane-sulfonic anhydride and an appropriate base. Both compounds R1xe2x80x94OH and R1xe2x80x94J are used in the methods portrayed in Scheme 1. Conversion of R1xe2x80x94J to R1xe2x80x94N3 requires the use of an azide source, such as sodium azide, and a solvent such as dimethylsulfoxide or dimethylformamide, or water and a phase-transfer catalyst (such as tetrabutylammonium hydrogen sulfate). Reduction of the azide compound R1xe2x80x94N3 to R1xe2x80x94NH2 may be accomplished using reagents such as sodium borohydride or triphenylphosphine, or hydrogen gas and a catalyst (such as palladium on carbon). The amine R1xe2x80x94NH2 may then be employed in the methods portrayed in Scheme 6.
In the cases where the compound R1xe2x80x94OH could be represented by a structure of formula (XXI) (Scheme 8), wherein R1a and R1b represents substructures which, taken together with the carbinol methine group, comprise the entire group R1, this compound may be prepared by addition to a carbonyl compound. 
This route is particularly useful in the case where R1a or R1b represents a cycloalkyl group, such as cyclopropyl. An organometallic reagent (where Mxe2x80x2 represents a metallic group, such as Li, CUCN, CuI, MgCl, MgBr, MgI, ZnCl, CrCl, etc.) can be allowed to react with an aldehyde reagent to prepare the alcohol compound of formula (XXI). Alternatively, a ketone of formula (XXII) may be treated with a reducing agent, such as sodium borohydride, lithium aluminum hydride, etc., which will also generate the alcohol of formula (XXI). Standard methods of ketone synthesis may be used where appropriate in the preparation of compounds for formula (XXII), which will be familiar to those skilled in the art of organic synthesis.
An homologous approach may also be employed in the synthesis of alcohols R1xe2x80x94OH, involving the ring-opening reaction of cyclic ether compounds with organometallic reagents (Scheme 9). 
Here, an organometallic reagent R1axe2x80x94Mxe2x80x3 is used, where Mxe2x80x3 represents metals such as Mg, Zn or Cu. Especially useful is the method described in Huynh, et al., Tetrahedron Letters 1979, (17), pp. 1503-1506, where organomagnesium reagents are allowed to react with cyclic ethers with catalysis provided by copper (I) iodide. Use of an epoxide compound of formula (XXIII) in this manner would result in synthesis of an alcohol compound of formula (XXIV), and use of an oxetane compound of formula (XXV) would generate an alcohol of formula (XXVI). Both compounds (XXIV) and (XXVI) are variants of R1xe2x80x94OH.
Synthesis of compound R1xe2x80x94NH2 with formula (XXVII) is portrayed in Scheme 10. 
A simple reductive amination of ketone (XXII) will produce amine (XXVII). This reaction may be performed using anhydrous ammonia in the presence of hydrogen and a catalyst. Alternatively, addition of an organometallic reagent to a nitrile compound gives and imine, which may be treated in situ with a reducing agent (such as sodium cyanoborohydride) to give amine (XXVII). Finally, a compound of formula (XXVIII), wherein Q is an optionally-substituted oxygen atom (i.e. an oxime) or nitrogen atom (i.e. a hydrazone), may be allowed to react with an organometallic reagent R1bxe2x80x94Mxe2x80x2xe2x80x3. Here, metallic groups Mxe2x80x2xe2x80x3 such as MgBr, CuCl or CeCl2 have been used in additions to oximes or hydrazones. The intermediate addition products of formula (XXIX) may be subjected to reductive cleavage (using conditions such as sodium/liquid ammonia or catalytic hydrogenation), which will afford amines (XXVII).
Amino acids, either naturally-occurring or synthetic, are potential sources of useful starting materials for the synthesis of the compounds of this invention. Scheme 11 shows some possible applications of this approach. 
Protected amino acids of formula (XXXI) are prepared from the parent compounds of formula (XXX); useful protecting groups (xe2x80x9cProtxe2x80x9d) include tert-butoxycarbonyl, benzyloxycarbonyl and triphenylmethyl. Standard texts in peptide chemistry describe this protection. The carboxylic acid group may be reduced using reagents such as lithium borohydride, which gives alcohol (XXXII). The hydroxy group may be converted to a leaving group xe2x80x9cJxe2x80x9d as described before. The compound of formula (XXXIII) may be treated with appropriate reagents to produce a wide variety of functional groups included in the scope of this invention (compound (XXXIV)); displacement of J with cyanide (sodium cyanide in warm dimethylformamide may be used here) gives a nitrile, displacement of J with a mercaptan (in the presence of a base, such as potassium carbonate) gives a disulfide, displacement of J with a secondary amine gives a tertiary amine, etc.
The compounds of Formula (I) with unsaturated R1 groups can be a further source of compounds covered under this invention. Unsaturated (double and triple) bonds can take part in cycloaddition chemistry with appropriate reagents (Scheme 12). Cycloaddition of an alkyne compound of Formula XXXVI with 1,3-dienes to give six-membered ring compounds like that of Formula XXXVII (commonly known as the Diels-Alder reaction), and cycloaddition with 3-atom dipolar reagents to give heterocyclic compounds of Formula XXXVIII, are familiar to those skilled in the art of organic synthesis. One specific example of this approach is the synthesis of an isoxazole compounds of Formula XXXIX from the alkyne XXXVI and a nitrile oxide reagent. 
The synthetic procedure in Scheme 13 shown below may be used to prepare 4,5-c imidazopyridines. 
Nitration of 2,4-dihydroxypyridine (XXXX) with HNO3 as described earlier (Koagel et al. Recl. Trav. Chim. Pays-Bas. 29, 38, 67, 1948) gave the corresponding 3-nitropyridone (XXXXI) which was treated with an organic amine base, such as cycloheptyl amine to give selectively the corresponding 4-chloropyridone (XXXXIII). This in turn was reacted with a primary amine RNH2, where R is a group described earlier in an aprotic or protic solvent, such as CH3CN, DMSO, DMF, or an alkyl alcohol in the presence of an organic or inorganic base, such as a trialkylamine, K2CO3, Na2CO3 etc, and in temperature range of 20-200xc2x0 C. to give the 4-amino adduct (XXXXIII). Pyridone (XXXXIII) was converted to the 2-chloropyridine (XXXXIV) by treatment with POCl3, and (XXXXIV) was coupled with an arylboronic acid ArB(OH)2 under palladium catalysis to give (XXXXV). Nitropyridine (XXXXV) was reduced to the corresponding aminopyridine by use of Na2S2O4 or a Fe, Sn or SnCl2 and converted to the imidazo[4,5-c]pyridine in refluxing propionic acid. The same transformation can be affected by the use of a nitrile, an imidate, thioimidate or trialkylorthopropionate.
The synthetic procedure in Scheme 14 shown below may be used to prepare 4,5-b imidazopyridines. 
Reaction of 4-chloropyridone (XXXXII) with an aryl halide, such as benzyl bromide in benzene and in the presence of Ag2CO3 as described in Scheme 13 (Smith A. M.; et al. J. Med. Chem. 36, 8, 1993) and at temperature ranges of 30-80xc2x0 C. afforded the corresponding 2-benzyloxypyridine (XXXXVII). This was coupled with an arylboronic acid, ArB(OH)2 under palladium-catalyzed conditions to give (XXXXIX). The benzyloxy group can be removed by treatment with a strong acid, such as trifluoroacetic, triflic, sulfuric, HCl, etc. to give pyridone (L). This was converted to the 2-halopyridine with the action of POX3, PX5 or the corresponding triflate, tosylate or mesylate, which was displaced with a primary amine RNH2 to give (LI). The nitro group was reduced under conditions described in scheme 13 and the aminopyridine was cyclized to the imidazolo[4,5-b]pyridine (LII) under conditions described in scheme 13.